Radiotheranostic landscape: A review of clinical and preclinical development.pdf

Radiotheranostic landscape: A review of clinical and preclinical development.pdf

1. Vol.:(0123456789) European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
https://doi.org/10.1007/s00259-025-07103-7
REVIEW ARTICLE
Radiotheranostic landscape: A review of clinical and preclinical
development
Ha H. Tran
1
 · Aiko Yamaguchi
1
 · H. Charles  Manning
1,2
 
Received: 4 November 2024 / Accepted: 20 January 2025 / Published online: 1 February 2025
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025
Abstract
Background  Radiotheranostics combines diagnostic imaging with targeted radionuclide therapy, representing a transformative approach
in precision oncology. Landmark approvals of ­ Lutathera
®
 and ­Pluvicto
®
 have catalyzed signicant advancements in this eld, driving
research into novel radionuclides, targeting strategies, and clinical applications. This review evaluates the evolving clinical and pre-
clinical landscape of radiotheranostics, highlighting advancements, emerging trends, and persistent challenges in radionuclide therapy.
Methods  A comprehensive analysis was performed, encompassing active clinical trials as of December 2024, sourced from
ClinicalTrials.gov and TheranosticTrials.org. Preclinical developments were evaluated through a review of recent literature,
focusing on innovations in radionuclide production, targeting molecules, and radiochemistry.
Results  In reviewing the clinical landscape, agents targeting somatostatin receptors (SSTR) and prostate-specic membrane
antigen (PSMA) still dominate the eld, but new targets such as broblast activation protein (FAP), integrins, and gastrin-
releasing peptide receptors (GRPR) are gaining traction in both clinical and preclinical development. While small mol-
ecules and peptides remain the most common radionuclide carriers, antibody-based carriers including bispecic antibodies,
immunoglobin-derived antigen-binding fragments, and antibody-mimetic proteins are on the rise due to their specicity and
adaptability. Innovations in radioligand design are driving a shift from agonists to antagonists, accompanied by the devel-
opment of modied peptides with enhanced pharmacokinetics and tumor-targeting properties. Next-generation therapeutic
radionuclides, such as the beta-emitter terbium-161 and alpha-emitters actinium-225 and lead-212, are under investigation to
complement or replace lutetium-177, addressing the need for improved ecacy and reduced toxicity. Paired isotopic radio-
nuclides are gaining popularity for their ability to optimize imaging and therapeutic dosimetry as they oer near-identical
specicity, biodistribution, and metabolism. Additionally, radiohybrid systems represent an innovative approach to chelat-
ing chemically distinct radionuclide pairs within a single molecule, further enhancing exibility in radiotheranostic design.
Conclusion  Radiotheranostics has transformed cancer care through its precision and adaptability, but challenges in radionuclide
production, regulatory frameworks, and workforce training hinder broader adoption. Advances in isotopic pairing, next-generation
radionuclides, and radiohybrid systems in preclinical and clinical settings hold promise to overcome these barriers. Collaborative
eorts among academia, industry, and regulatory bodies are critical to accelerating innovation and optimizing clinical outcomes.
Keywords  Radiotheranostics · Radiopharmaceuticals · Targeted radionuclide therapy · Somatostatin receptors · Prostate-
specic membrane antigen? Radioimmunoconjugates? Alpha emitters? Isotopic radionuclide pairs
* H. Charles Manning
[email protected]
1
Department of Cancer Systems Imaging, The University
of Texas MD Anderson Cancer Center, Houston, TX, USA
2
Cyclotron Radiochemistry Facility, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA
Introduction
Radiotheranostics is a rapidly growing cancer treatment modal-
ity characterized by the two-pronged approach of pairing
molecular imaging with targeted therapy [1 ]. A tracer labeled
with an imaging radionuclide emitting positron or gamma ray
can capture tumor burden, assess the therapeutic index, and
assist with patient stratication via positron emission tomog-
raphy (PET) or single photon emission computed tomography
(SPECT) imaging [2 ]. A second agent where the same targeting

2. 2686 European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
moiety is labeled with a therapeutic radionuclide can bind and
kill cancer cells via lethal high-energy radiation [3 ] (Fig. 1).
The ability to visualize tumors, identify areas likely to respond,
and monitor treatment eectiveness make radiotheranostics one
of the most precise and personalized therapies to date.
The past decade has witnessed exponential development in
the eld, with two signicant radiotheranostic agents approved
for cancer treatment. In 2018, the U.S. Food and Drug Admin-
istration (FDA) and the European Medicines Agency (EMA)
approved Lutathera® ­ ([
177
Lu]Lu-DOTATATE) for neuroendo-
crine tumors aecting the digestive tract (GEP-NET) [4]. ­[
177
Lu]
Lu-DOTATATE is accompanied by imaging agents ­ [
68
Ga]Ga-
DOTATATE or ­ [
64
Cu]Cu-DOTATATE in the U.S., and ­ [
68
Ga]
Ga-DOTATOC in the EU, providing a fully integrated diagnos-
tic and therapeutic solution [5 ]. In 2022, Pluvicto® ­ ([
177
Lu]Lu-
PSMA-617) and its imaging counterpart ­ [
68
Ga]Ga-PSMA-11
received FDA and EMA approvals for the treatment of meta-
static castration-resistant prostate cancer (mCRPC), a prevalent
and advanced form of prostate cancer [6 ]. These approvals have
catalyzed signicant interest and investment from the pharma-
ceutical industry, driving innovations in radionuclides, targeting
agents, and clinical applications, further expanding the radio-
theranostic eld.
Since these landmark approvals, the industry has invested
heavily in scaling production and developing new radiopharma-
ceuticals. Key players like Novartis, Bayer, and GE Healthcare
have made strategic partnerships and investments to enhance
manufacturing capacities, streamline regulatory processes, and
bring radiotheranostic agents to broader patient populations.
Novartis, for example, has expanded its production facilities and
signicantly increased the availability of Pluvicto?, while others
are working to develop new α-emitting agents, novel targeting
strategies, and combination therapies. These eorts reect a col-
lective commitment to advancing radiotheranostics, overcoming
production and regulatory challenges, and enhancing the treat-
ment options available for patients with cancer.
Despite recent advances, the landscape remains highly
dynamic and fragmented, necessitating a comprehensive
Fig.1  Principles of radiotheranostics: See what you treat and treat
what you see. A radiotheranostic agent contains a carrier molecule
targeting a tumor-specic receptor or antigen labeled with a diagnos-
tic radionuclide or a therapeutic radionuclide with or without a linker.
Diagnostic radiotracers emit positrons or gamma rays and allow for
tumor visualization, patient stratication, and therapeutic dosimetry
through positron emission tomography (PET) or single photon emis-
sion computed tomography (SPECT) imaging. Therapeutic radiotrac-
ers tag and kill cancer cells via lethal α or β
−
radiation. BFC: bifunc-
tional chelating agent. Created with BioRe nder. com

3. 2687European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
review to consolidate current knowledge. Existing literature
often focuses on specic components, such as individual radi-
onuclides or carrier molecules, without providing a holistic
overview of clinical and preclinical developments. Addition-
ally, emerging trends such as α emitters, isotopic matching,
and next-generation radionuclide carriers are reshaping the
eld but remain underexplored in the context of their broader
implications. Furthermore, challenges such as radionuclide
production limitations, regulatory complexities, and barriers
to clinical translation underscore the need for a critical analy-
sis to identify gaps and opportunities for future research. This
review addresses these gaps by systematically evaluating the
current radiotheranostic landscape, clinically and preclinically,
oering an updated perspective on key advancements, trends,
and challenges. By highlighting the integration of novel tech-
nologies and therapeutic strategies, this review aims to provide
a roadmap for researchers, clinicians, and industry stakehold-
ers to navigate the complexities of this rapidly evolving eld
and accelerate the translation of radiotheranostics into clinical
practice.
Clinical assessment
To provide a comprehensive perspective of the current clini-
cal utilization of radiotheranostics, we screened clinical trial
databases from the National Library of Medicine’s registry
Clini calTr ials. gov and Thera nosti cTria ls. gov (Supplementary
Fig.2  Assessment of targeted radiotherapy agents in clinical devel-
opment. Across components of assets in active clinical trials, the
top ten targets (A), therapeutic radionuclides (B), all seven types of
carriers (C), and the top ten cancer types (D) are shown. See Sup-
plementary Figure  S2 for an expanded version. SSTR: somatostatin
receptor, PSMA: prostate-specic membrane antigen, FAP: broblast
activation protein, Bone mets: bone metastasis, NE: norepinephrine,
GRPR: gastrin-releasing peptide receptor, CAIX: carbonic anhydrase
IX, NIS: Sodium-iodine symporter, CNS: central nervous system,
N.a.: Not applicable

4. 2688 European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
Figure S1). All active clinical trials involving radionuclide ther-
apy as of December 2024 were categorized based on molecular
targets, therapeutic radionuclides, carrier molecules, and cancer
types (Fig. 2). This review solely focuses on therapeutic radionu-
clides, therefore, trials involving only imaging radionuclides are
excluded. Of note, a few radiopharmaceuticals are considered
radionuclide therapy agents but not radiotheranostics if there is
no paired imaging component. Diusing alpha-emitter radia-
tion therapy (DaRT) and microspheres with radium-224 (
224
Ra),
bone metastasis-targeting radium-233 (
223
Ra) dichloride, and
yttrium-90 (
90
Y) radioembolization are some examples. These
radiopharmaceuticals are excluded from our further analysis and
discussion.
Among the 277 trials we identied, the most popular targets
remained somatostatin receptor (SSTR) and prostate-specic
membrane antigen (PSMA) (Fig. 2A). For these targets, cur-
rent clinical trials are designed to move ­ [
177
Lu]Lu-DOTA-
TATE and ­ [
177
Lu]Lu-PSMA-617 to earlier lines of treatment,
combine them with other drugs, test their eectiveness in unli-
censed indications, test new targeted agents that have improved
pharmacokinetics and/or toxicity prole, and new targeted
agents with dierent radionuclides. Besides SSTR and PSMA,
other tumor-specic membrane proteins, including broblast
activation protein (FAP), integrins, gastrin-releasing peptide
receptor (GRPR), carbonic anhydrase IX (CAIX), and multiple
CD markers are examples of clinical targets.
Due to validated success and optimized clinical produc-
tion, lutetium-177 (
177
Lu) dominates other therapeutic radi-
onuclides in current clinical targeted radionuclide therapy
(TRT) agents (Fig. 2B). At the same time, actinium-225
(
225
Ac) has seen increasing interest as it is the most popular
α emitter and the third most popular therapeutic radionu-
clide. Looking at current clinical assets,
177
Lu remained the
rst choice when exploring emerging targets. In contrast,
radionuclides other than the
68
Ga/
177
Lu pair mainly target
SSTR and PSMA. Other clinical therapeutic radionuclides
include
90
Y, iodine-131 (
131
I), lead-212 (
212
Pb), copper-67
(
67
Cu), terbium-161 (
161
Tb), and astatine-211 (
211
At), with
clinical popularity in that order.
Small molecules and peptides are the most common tar-
geting moieties. This is primarily because of the large num-
ber of trials involving ­ [
177
Lu]Lu-DOTATATE and ­ [
177
Lu]
Lu-PSMA-617. Additionally, a sizable portion of these trials
involves many new SSTR- and PSMA-targeting modied
peptides and small molecules that possess better binding
or tumor uptake properties than the commercial agents
(Fig. 2C). The antibody portfolio follows small molecule
and peptide with 38 agents in clinical trials, most are full-
length monoclonal antibodies (mAbs). However, there is one
bispecic antibody (NCT06147037), one fragment antibody
binding (Fab) domain (NCT05533242), and three nanobod-
ies (NCT04674722, NCT05982626, NCT06305962). All
ve are in the early phases of clinical validation.
The current focus on SSTR and PSMA also creates a
bias on prostate and neuroendocrine tumors as indications
(Fig. 2D). Cancers of the central nervous system, including
glioblastoma, neuroblastoma, and meningioma are next on
the list because SSTR is also found to be highly expressed
in these tumors [7 ]. Radiotheranostic agents used in hema-
tological malignancies including multiple myeloma, lym-
phoma, and leukemia are commonly targeted with repur-
posed commercial antibodies (for example, NCT05363111,
NCT02342782, NCT04512716). A wide range of carcino-
mas including breast, lung, nonmelanocytic skin, pancreatic,
head and neck, and liver and bile duct cancer with diverse
membrane targets represents a large class of emerging indi-
cations that could benet from radiotheranostics.
Clinical radionuclides
Based on their main decay modes, therapeutic radionu-
clides in clinical trials can be categorized into two groups
– β
−
emitters and α emitters. β
−
-emitting radionuclides emit
electrons (β
−
particles) via β
−
decay, where a neutron is con-
verted into a proton, an electron, and an electron antineu-
trino. α emitters
225
Ac,
211
At, or
212
Pb’s daughter radionu-
clide
212
Bi emit α-particles ­ (He
2+
) via nuclear transmutation
by α-decay. Compared to β
−
particles, α-particles are larger
and heavier, less penetrating but more damaging to cells and
DNA [8 ]. Some radionuclides decay by electron capture and
internal conversion, accompanied by ejection of low-energy
electrons via the Auger eect, so-called Auger electron (AE)
emitters. Terbium-161 (
161
Tb) is the only radionuclide in
trials with AE as one of its major decay modes. Although
its half-life and decay characteristics are comparable to
177
Lu, the signicant emission of conversion and AE par-
ticles makes
161
Tb a more potent therapeutic agent, espe-
cially for minimal residual disease [9 ]. Several studies have
demonstrated that substituting
177
Lu with
161
Tb can deliver
higher doses to tumors [10, 11]. For example, a recent pilot
study in six heavily pre-treated mCRPC patients comparing
­[
161
Tb]Tb-PSMA-617 with ­ [
177
Lu]Lu-PSMA-617 showed
that
161
Tb oers higher local dose densities and improved
tumor targeting, supporting its potential as a superior radioli-
gand therapy option for further investigation [12]. While the
results look promising, scaling up the production of
161
Tb
and ensuring consistent supply quality remain critical chal-
lenges for its broader clinical application.
Paired imaging radionuclides typically leverage PET
due to its superior imaging capabilities over SPECT sys-
tems [13] (Table  1). As a result, positron emitters such
as gallium-68 (
68
Ga), followed by uorine-18 (
18
F), cop-
per-64 (
64
Cu), zirconium-89 (
89
Zr), and iodine-124 (
124
I)
are most used in clinical trials. However, while PET cur-
rently dominates in clinical applications, SPECT is see-
ing a resurgence due to its distinct advantages, especially

5. 2689European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
in dosimetry and follow-up imaging. One key benet of
SPECT is its ability to utilize gamma-ray-emitting thera-
peutic radionuclides for post-therapy imaging, even though
the gamma emission is relatively limited. This feature
makes SPECT valuable for monitoring treatment response
without the need for additional imaging radionuclides
[14]. For example, several PSMA-targeting TRT agents are
in trials for both therapy and post-therapy imaging, includ-
ing ­[
177
Lu]Lu-PSMA-617 and ­ [
177
Lu]Lu-PSMA-I&T. A
recent report in 2024 indicates that SPECT/CT imaging
using ­[
177
Lu]Lu-PSMA-617 or ­ [
177
Lu]Lu-PSMA-I&T in
23 mCRPC patients is highly similar to baseline PET/CT
imaging using ­ [
68
Ga]Ga-PSMA-11 (Pearson’s p = 0.964
and 0.948) at 24 h post-injection [15].
In 168 clinical trials utilizing
177
Lu, 82 involve new
radiotheranostic agents, of which 43 are SSTR- or PSMA-
targeting agents, 13 for SSTR, and 30 for PSMA. The
remaining 37 trials involve agents for targets other than
SSTR and PSMA, accounting for about half of the clinical
studies for novel targets. On the other hand, of 25 trials
with
225
Ac, 14 are TRT agents targeting SSTR or PSMA.
A similar trend was seen with other therapeutic radio-
nuclides, further indicating the dominance of SSTR and
PSMA-targeting agents in the clinical portfolio.
Lutetium-177 is the most-used β
−
emitter with a maxi-
mum β
−
energy of 497 keV and a half-life of 6.65 days,
compatible with both antibodies and peptides [22]. This
radionuclide also emits gamma photons at 208 keV and
113 keV [22], enabling SPECT imaging to map the phar -
macokinetics of TRT agents. Lutetium-177 has a mean route
length of 0.16 mm and a maximum tissue penetration depth
of 2 mm, which equals 20 to 60 cells [23, 24]. Compared to
other therapeutic radionuclides,
177
Lu has a relatively long
half-life and short-range emission, making this β
−
emitter
favorable for TRT, especially in treating small tumors [17].
Other β
−
emitters in trials include
90
Y,
131
I, and
67
Cu, each
with advantages and disadvantages. Shorter range β
−
emit-
ters
131
I and
67
Cu are also suitable for small tumors, but
Table1   Isotope pairing seen in clinical trials
*
212
Pb: Decays to α-particle emitting
212
Bi via β
−
particle emission. ­ E
max
: Max ɑ/β energy per decay. NCT references are non-exhaustive exam-
ples and do not include all trials with respective pairings.
Therapeutic
radionuclide
Emission (half-life) [16] E
max
Imaging radionuclideEmission (half-life) [13] Carrier (NCT reference)
177
Lu β
−
(6.65 days) 497 keV [17]
68
Ga β
+
(67.8 min) Small molecule (approved), peptide
(approved)
64
Cu β
+
(12.7 h) Peptide (approved)
89
Zr β
+
(3.27 days) Antibody (NCT05239533,
NCT05868174)
225
Ac α (9.92 days) 8.4 MeV [18]
68
Ga β
+
(67.8 min) Small molecule (NCT05983198),
antibody (NCT04506567,
NCT04946370)
111
In γ (2.81 days) Small molecule (NCT05605522,
NCT04597411), antibody
(NCT03746431, NCT06147037)
131
I β
−
(8.02 days) 606 keV [17]
124
I β
+
(4.17 days) None (NCT00673010), small molecule
(NCT03784625)
123
I γ (13.2 h) Small molecule (NCT03561259)
68
Ga β
+
(67.8 min) Nanobody (NCT05982626)
99m
Tc γ (6.04 h) Small molecule (NCT03784625)
90
Y β
−
(2.67 days) 2.3 MeV [17]
68
Ga β
+
(67.8 min) Peptide (NCT03044977)
111
In γ (2.81 days) Peptide (NCT05568017,
NCT03044977), antibody
(NCT04856215)
67
Cu β
−
(2.58 days) 562 keV [17]
64
Cu β
+
(12.7 h) Small molecule (NCT04868604,
NCT05633160), peptide
(NCT04023331, NCT03936426)
212
Pb* α (10.6 h) 7.3 MeV [19]
203
Pb γ (2.17 days) Peptide (NCT05655312,
NCT05557708)
68
Ga/
18
F β
+
(67.8 min/109.7 min)Small molecule (NCT05720130)
161
Tb β
−
(6.95 days) 593 keV [20]
68
Ga β
+
(67.8 min) Small molecule (NCT05521412),
peptide (NCT05359146)
211
At ɑ (7.21 h) 7.5 MeV [21]
68
Ga β
+
(67.8 min) Small molecule (NCT06359821)

6. 2690 European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
the intermediate physical half-life of
67
Cu ­(t
1/2
 = 2.58 days)
[17] and the shortened biological half-life of
131
I due to
dehalogenase [25] make them less favorable. However,
both therapeutic radionuclides have isotopically matched
imaging radionuclides,
64
Cu and
123,124
I, respectively, giv-
ing them an edge over
177
Lu.
90
Y has a longer range and is
more energetic, making this radionuclide more suitable for
larger tumors, though its intermediate half-life of 2.67 days
is a limitation [17].
The rising α emitter,
225
Ac, emits four net α-particles per
decay, has high linear energy transfer (LET), limited radia-
tion range in tissue, and a physical half-life of 9.92 days,
allowing time for chelation, administration, and accumula-
tion at tumor sites [8 ]. With a maximum α energy per decay
of 8.4 MeV [26],
225
Ac is signicantly more ecacious than
177
Lu because it causes more tissue damage and has a higher
rate of creating DNA double-strand breaks. The
225
Ac route
length is comparably lower at 47 to 85 µm in human tis-
sue [18], leading to potentially less damage to surrounding
non-tumor cells and lower o-tumor toxicity. Two other α
emitters seen in clinical trials,
211
At and
212
Pb, have half-
lives of less than 12 h and are more suited to labeling small
molecules and peptides. Because of their quick decay, the
use of these short-lived radionuclides in radiotheranostics is
currently limited, and broadly applicable production has not
yet reached the maturity of other isotopes [27, 28].
Clinical targets
SSTR‑ and PSMA‑targeting agents
While Lutathera® and Pluvicto® were approved as mono-
therapies, combination therapies are emerging as a powerful
strategy to enhance the ecacy of these agents, address tumor
heterogeneity, and overcome resistance mechanisms (Supple-
mentary Table S1). In 83 trials for SSTR-targeting agents, 18
are testing ­ [
177
Lu]Lu-DOTATATE combined with other agents,
including anti-PD-1/PD-L1 antibodies, chemotherapy agents,
and other TRT agents. Notably, a phase I/II study co-adminis-
tering ­[
177
Lu]Lu-DOTATATE and
131
I-labeled metaiodoben-
zylguanidine (
131
I-MIBG) for mid-gut NETs is a rst-in-human
study to combine two TRT agents (NCT04614766), with a
dosing schedule tailored to each patient. Another signicant
aspect of current trials involving these approved agents is their
incorporation with standard-of-care (SOC) treatments to move
them into earlier lines of therapy, potentially improving patient
outcomes. NETTER-2 (NCT03972488) is an open-label, rand-
omized phase III trial combining ­ [
177
Lu]Lu-DOTATATE with
octreotide as rst-line treatment for GEP-NET patients. Results
from this study showed that this combination extended median
progression-free survival (PFS) by 14 months in patients with
newly diagnosed grade 2 or 3 advanced GEP-NETs [29]. More
ongoing trials combining or comparing ­ [
177
Lu]Lu-DOTATOC
with SOC treatments such as COMPETE (NCT03049189) and
COMPOSE (NCT04919226) can further help transform the
treatment sequence of GEP-NETs.
For the newly approved ­ [
177
Lu]Lu-PSMA-617, a nota-
ble example of moving this agent to the early line of treat-
ment is PSMAfore (NCT04689828), a phase III, open-label,
multi-center, 1:1 randomized study testing the potential of
­[
177
Lu]Lu-PSMA-617 for treating mCRPC taxane-naïve
patients. The primary endpoint was met with median radio-
graphic progression-free survival (rPFS) of 9.30 months for
the ­[
177
Lu]Lu-PSMA-617 group and 5.55 months for the
SOC group (HR = 0.41, 95% CI  = 0.29–0.56) [30]. Simi-
lar to ­[
177
Lu]Lu-DOTATATE, ­[
177
Lu]Lu-PSMA-617 is the
focus of many clinical trials, with combinations being tested
alongside androgen receptor pathway inhibitors (ARPIs),
hormone therapy, radiotherapy, anti-PD-1 antibodies, and
other targeted therapies. While ARPIs, hormone therapy,
and radiotherapy are SOC for prostate cancer, combining
­[
177
Lu]Lu-PSMA-617 with other targeted agents and immu-
notherapies is being explored for multiple reasons—to target
dierent aspects of tumor biology, to enhance tumor-specic
delivery, and to activate immune responses against resistant
tumor populations. This approach reects a growing under-
standing that multi-modal treatments may oer a more com-
prehensive solution to overcoming cancer’s complex resist-
ance mechanisms, thereby improving therapeutic ecacy
and patient outcomes.
For ­[
177
Lu]Lu-PSMA-617, a signicant number of trials
are also exploring dose adjustment, frequency of therapy,
or tandem usage of dierent radionuclides, all designed to
overcome radioresistance or reduce toxicity. A phase I dose
escalation study (NCT03042468) has recently shown that a
dose-dense fractionation schedule is safe and led to signi-
cant PSA decline compared to the current less dose-intense
approach [31]. This denser dosing schedule allows the deliv-
ery of higher total doses, which could overcome radiore-
sistance caused by the repopulation of PSMA. Similarly,
shorter treatment interval, 2 to 5 cycles within four-week
intervals compared to the standard one xed dose within
six-week intervals of the landmark VISION trial, was shown
to improve survival without inducing toxicity [32]. Tandem
use of
225
Ac and
177
Lu is being explored in multiple trials
for patients not responding to
177
Lu therapy. While the α
emitter has shown greater therapeutic ecacy, it also causes
higher toxicity, such as the dose-limiting xerostomia seen
in patients treated with ­ [
225
Ac]Ac-PSMA-617 [33]. As a
workaround to balance ecacy and toxicity, tandem use of
­[
177
Lu]Lu-PSMA-617 and ­ [
225
Ac]Ac-PSMA-617 is under
investigation, with early results indicating synergy between
the two radionuclide drugs [34].
A substantial number of clinical trials are investigat-
ing ­[
177
Lu]Lu-DOTATATE and ­ [
177
Lu]Lu-PSMA-617
for indications beyond their currently approved uses.

7. 2691European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
For ­[
177
Lu]Lu-DOTATATE, ongoing trials are explor-
ing its efficacy in treating many SSTR-positive tumors
including meningioma (NCT04082520, NCT03971461,
NCT06126588, NCT06326190), neuroblastoma
(NCT04903899, NCT03966651), pheochromocytoma and
paragangliomas (PPGL; NCT04711135, NCT03206060),
glioblastoma (NCT05109728), recurrent breast can-
cer (NCT04529044), metastatic Merkel cell carcinoma
(NCT04261855), and extend-stage small cell lung cancer
(ES-SCLC, NCT05142696). Similarly, studies of ­ [
177
Lu]
Lu-PSMA-617 in other types of prostate cancer include
metastatic hormone-sensitive prostate cancer (mHSPC,
NCT04443062, NCT04720157, NCT05079698), metastatic
hormone-naïve prostate cancer (mHNPC, NCT04343885),
localized or locoregional advanced prostate cancer
(HRCaP, NCT04430192), node-positive prostate cancer
(NCT05162573). A noteworthy trial for unlicensed indica-
tion is Novartis’s phase I trial for metastatic neuroendocrine
prostate cancer (NCT06379217), where patients will be
screened with three radioligand imaging compounds ­ ([
68
Ga]
Ga-DOTATATE, ­[
68
Ga]Ga-PSMA-11, ­[
68
Ga]Ga-NeoB) to
assess the expression levels of SSTR2, PSMA, and GRPR.
Patients will then be assigned to the radioligand treatment
target ­([
177
Lu]Lu-DOTATATE, ­[
177
Lu]Lu-PSMA-617,
­[
177
Lu]Lu-NeoB) corresponding to their predominantly
expressed without crossover with another agent throughout
the treatment period. Overall, these studies aim to expand
the clinical utility of commercial agents with known toxic-
ity proles and mechanisms of action to a broader range of
tumors with high unmet medical needs.
Besides ­[
177
Lu]Lu-DOTATATE and ­ [
177
Lu]Lu-
PSMA-617, several new SSTR- and PSMA-targeting agents
have entered clinical trials to compete with the commercial
agents. For SSTR, DOTATOC has been a long-time com-
petitor with DOTATATE, and many studies with ­ [
177
Lu]Lu-
DOTATOC and ­ [
90
Y]Y-DOTATOC are ongoing. As DOTA-
TATE was shown to be more ecacious than DOTATOC in
treating GEP-NETs, current trials focus on testing ­ [
177
Lu]
Lu-DOTATOC in neuroendocrine neoplasia not originat-
ing from the digestive tract (NCT04917484, NCT05387603,
NCT06045260), and testing ­ [
90
Y]DOTATOC in preoperative
NETs (NCT05568017) or in combination with
131
I-MIBG
(NCT03044977) in mid-gut NETs. ­ [
90
Y]Y-DOTATOC
was previously tested in hepatic metastases of NETs
(NCT03197012), where it showed a lack of ecacy despite
hepatic intraarterial administration [35]. Another notable
SSTR-targeting agent is ­ [
67
Cu]Cu-SARTATE, currently in
trials for pediatric neuroblastoma (NCT04023331) along
with its isotopic imaging agent ­ [
64
Cu]Cu-SARTATE. Results
from the phase I/II trial in meningioma (NCT03936426)
showed that PET imaging and on-therapy SPECT imaging
were nearly identical [36], demonstrating a potentially accu-
rate and precise radiotheranostic pairing that could give the
64
Cu/
67
Cu pair an advantage over the commercial
68
Ga/
177
Lu
pair.
For ­[
177
Lu]Lu-PSMA-617, because this agent was only
recently approved and prostate cancer is one of the most
prevalent cancers in men, many new PSMA-targeting radi-
opharmaceuticals with modied structures or chelated to
other radionuclides have entered clinical trials to compete
(Table 2). For example, ­ [
177
Lu]Lu-PSMA-I&T is a DOT-
AGA-chelated urea-based PSMA inhibitor with a exible
and adjustable linker scaold [37] that is currently in nine
clinical trials. In a retrospective study, matched-pair analy-
sis of ­ [
177
Lu]Lu-PSMA-617 and ­ [
177
Lu]Lu-PSMA-I&T
in patients with mCRPC showed comparable low toxicity
levels as well as similar overall survival (OS) in patients
treated with one of the two agents [37]. An ongoing multi-
center, open-label, randomized, phase III trial, ECLIPSE
(NCT05204927), is comparing the safety and ecacy of
­[
177
Lu]Lu-PSMA-I&T to hormone therapy (abiraterone
with prednisone or enzalutamide) in patients with mCRPC.
PSMA-I&T agents labeled with
225
Ac and
161
Tb are also in
trials for mCRPC (NCT06402331, NCT05521412). Another
notable example is Convergent Therapeutics’ agent, ­ [
225
Ac]
Ac-J591 (CONV01-α), a PSMA-targeting mAb linked to
225
Ac that demonstrated safety and preliminary ecacy in
a phase I trial [38].
Novel targets
Besides SSTR and PSMA, many new targets have emerged
in the radiotheranostic space, 35 of which are being
tested in active clinical trials. Fibroblast activation pro-
tein (FAP) ranked third in clinical targets with 13 clini-
cal trials (NCT06197139, NCT05963386, NCT05723640,
NCT05410821, NCT06081322, NCT04849247,
NCT05432193, NCT04939610, NCT06211647,
NCT06553846, NCT06636617, NCT06640413,
NCT05400967). These clinical trials involve seven unique
FAP inhibitors (FAPIs) or FAP-targeting peptides for the
treatment of a range of FAP-positive solid tumors, all labeled
with
177
Lu. It has been shown that FAPI tracers labeled with
uorine-18 (
18
F) currently provide better diagnostic perfor-
mance than ­ [
18
F]FDG in certain cancers such as glioma, gas-
trointestinal tumors, liver tumors, oral squamous carcinoma,
and nasopharyngeal carcinoma [39]. Although
18
F-labeled
FAPI tracer has not replaced traditional ­ [
18
F]FDG in PET
imaging, some called it a potential ‘novel molecule of the
century’ due to its favorable imaging performance [40].
CAIX is a plasma membrane-associated carbonic anhy-
drase isoform with restricted expression in healthy tissues
but strong upregulation in almost all tumor tissues of solid
cancers [41]. CAIX interacts with acid/base transport pro-
teins and contributes to pH gradient reversal in the tumor
microenvironment (TME) by decreasing extracellular pH

8. 2692 European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
Table2   Novel PSMA-targeting radiotherapy agents in clinical trials
Radiotherapy agents RadionuclideCarrier moleculeImprovement over ­ [
177
Lu]Lu-
PSMA-617
NCT reference
[
177
Lu]Lu-PSMA-I&T
177
Lu Small moleculeModied structure with improved
pharmacokinetics
NCT05896371, NCT05867615,
NCT05893381,
NCT06343038,
NCT05204927,
NCT06220188,
NCT05521412,
NCT05644080,
NCT05230251
[
177
Lu]Lu-PSMA-1
177
Lu Small moleculeModied structure with improved
pharmacokinetics
NCT06059014
[
177
Lu]Lu-LNC1011
177
Lu Small moleculeModied structure with improved
pharmacokinetics
NCT06250244, NCT06377683
[
177
Lu]Lu-EB-PSMA-617
177
Lu Small moleculeModied structure with improved
pharmacokinetics
NCT03780075
[
177
Lu]Lu-LNC1003
177
Lu Small moleculeModied structure with improved
pharmacokinetics
NCT06237491
[
177
Lu]Lu-NYM032
177
Lu Small moleculeModied structure with improved
pharmacokinetics
NCT06383052
[
177
Lu]Lu-JH020002
177
Lu Small moleculeModied structure with improved
pharmacokinetics
NCT06139575
[
177
Lu]Lu-XT033
177
Lu Small moleculeModied structure with improved
pharmacokinetics
NCT06081686
[
177
Lu]Lu-DGUL
177
Lu Small moleculeModied structure with improved
pharmacokinetics
NCT05547061
[
177
Lu]Lu-PSMA-0057
177
Lu Small moleculeModied structure with improved
pharmacokinetics
NCT06050239
[
177
Lu]Lu-BQ7876
177
Lu Small moleculeModied structure with improved
pharmacokinetics
NCT06641219
[
177
Lu]Lu-Ludotadipep
177
Lu Small moleculeModied structure with improved
pharmacokinetics
NCT05579184, NCT05458544
[
177
Lu]Lu-HTK03170
177
Lu Small moleculeModied structure with improved
pharmacokinetics
NCT05570994
[
177
Lu]Lu-ITG-PSMA-1
177
Lu Small moleculeModied structure for automatized
in-hospital production
NCT05420727
[
177
Lu]Lu-rhPSMA-10.1
177
Lu Small moleculeModied structure with radiohybrid
ligand
NCT05413850, NCT06066437,
NCT06516510
[
161
Tb]Tb-SibuDAB
161
Tb Small moleculeDierent β
−
-emitting radionuclidesNCT06343038
[
131
I]I-1095
131
I Small moleculeDierent β
−
-emitting radionuclidesNCT03939689
[
67
Cu]Cu-SAR-bisPSMA
67
Cu Small moleculeDierent β
−
-emitting radionuclidesNCT04868604
[
225
Ac]Ac-PSMA I&T
225
Ac Small moleculeα-emitting radionuclide NCT05902247, NCT06402331
[
225
Ac]Ac-PSMA-R2
225
Ac Small moleculeα-emitting radionuclide NCT05983198
[
225
Ac]Ac-PSMA-62
225
Ac Small moleculeα-emitting radionuclide NCT06229366
[
225
Ac]Ac-PSMA-617
225
Ac Small moleculeα-emitting radionuclide NCT04597411
[
225
Ac]Ac-PSMA-Trillium
225
Ac Small moleculeα-emitting radionuclide NCT06217822
[
212
Pb]Pb-ADVC001
212
Pb Small moleculeα-emitting radionuclide NCT05720130
[
212
Pb]Pb-NG001
212
Pb Small moleculeα-emitting radionuclide NCT05725070
[
211
At]At-ZA-001
211
At Small moleculeα-emitting radionuclide NCT06359821
[
177
Lu]Lu-TLX591
177
Lu Humanized mAbDierent carrier molecule NCT05146973, NCT06520345
[
177
Lu]Lu-DOTA-rosopatamab
177
Lu Humanized mAbDierent carrier molecule NCT04876651
[
225
Ac]Ac-macropa-pelgifatamab
225
Ac Humanized mAbDierent carrier molecule,
α-emitting radionuclide
NCT06052306
[
225
Ac]Ac-J591
225
Ac Humanized mAbDierent carrier molecule,
α-emitting radionuclide
NCT04506567, NCT04576871,
NCT04946370

9. 2693European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
and increasing intracellular pH [41]. Extracellular acidi-
cation promotes tumor progression by killing adjacent
host cells, modifying cell–matrix adhesion, and suppress-
ing immunity; while intracellular alkalization fosters cell
proliferation and migration, and limits apoptosis [41]. Five
clinical trials involving CAIX-targeting agents include
one repurposed antibody (NCT05663710, NCT05239533,
NCT05868174), one peptide (NCT05706129), and one small
molecule (NCT06649682), all labeled with
177
Lu.
GRPR is a G protein-coupled receptor (GPCR) that binds
gastrin-releasing peptide and has been evaluated as a poten-
tial target in prostate cancer, breast cancer, and glioblastoma.
This receptor is targeted with bombesin derivatives labeled
with the radiotheranostic pairs
68
Ga/
177
Lu (NCT06247995,
NCT03872778, NCT05739942, NCT06379217) and
64
Cu/
67
Cu (NCT05633160), or the therapeutic radionuclide
212
Pb without an imaging component (NCT05283330), all
in phase I studies for safety assessment and dose-nding.
CD markers are surface molecules expressed on cells of
the immune system that play key roles in immune cell–cell
communication and sensing the microenvironment and
represent a group of attractive targets for radiotheranos-
tics. Multiple CD markers in clinical trials include CD45,
CD38, CD25, CD20, CD33, CD66, and CD19 for multiple
heme cancers, and CD44v6 for solid tumors. These are all
targeted by full-length mAbs labeled with either
177
Lu,
90
Y,
131
I,
225
Ac, or
211
At.
The last major group of targets with seven clinical trials
are integrins αvβ3, αvβ5, and αvβ6, three αv-family integ-
rins known for coordination of epithelial cell adhesion and
angiogenesis [42]. Five dierent
68
Ga/
177
Lu-labeled peptides
and peptidomimetics are all in the early stages of clinical
development for epithelial cancers. The αvβ6-targeting agent
­[
177
Lu]Lu-DOTA-ABM-5G currently has three clinical trials
(NCT06228482, NCT06389123, NCT04665947). Several
αvβ3-targeting agents include ­ [
177
Lu]Lu-DOTAGA-IAC
(NCT04469127), ­[
177
Lu]Lu-AB-3PRGD (NCT06375564),
αvβ3/αvβ5-targeting agent ­ [
177
Lu]Lu-FF58 (NCT05977322),
and αvβ3  × SSTR2-targeting heterodimeric peptide ­ [
177
Lu]
Lu-TATE-RGD (NCT06632873).
In summary, even though SSTR- and PSMA-targeting
agents still dominate current therapeutic clinical trials, the
number of TRT agents for novel targets is quickly rising, as
evidenced both in clinical trials and the diverse portfolio of
preclinical assets.
Expansion of the radiotheranostic landscape
The growing interest in radiotheranostics has led to an
increasing number of studies and publications (Supplemen-
tary Figure S3). From an industry perspective, the projected
annual growth rate of 14% and the projected value of more
than 6 billion USD by 2032 have led to increasing invest-
ment in the eld [43]. A few key players in R&D include
GE Healthcare Technologies, BAMF Health, RadioPharm
Theranostic Ltd., Clarity Pharmaceuticals, Point Biopharma
Global Inc., and Nuview Life Science, among others [43].
Herein, we take a closer look at their preclinical pipelines to
evaluate the future direction of the eld. A non-exhaustive
list of TRT agents for targets other than PSMA and SSTR
from disclosed pipelines that we found is summarized in
Table 3.
Target expansion
Emerging targets include the above-mentioned FAP, integ-
rins, CAIX, GRPR, and a few others. Besides FAP-targeting
agents seen in clinical trials listed above, many companies
are racing to push their agents into clinical trials. C-Biomex,
ITM Radiopharma, and Ratio Therapeutics each have one
FAP-targeting TRT agent in the discovery or preclinical
phase. In the early phase of development, most FAP-target-
ing molecules have a short retention time in tumor tissues,
making them more suitable for imaging but not therapy [64].
Contemporary FAP-targeting radiopharmaceuticals are mod-
ied FAPI, dimerized FAPI, or FAP peptides, all designed
to increase retention time in the TME [65].
For integrins, a few αv-series integrins are of interest,
most signicantly v6. Named the ?cancer integrin,? v6
expresses exclusively in epithelial cells, activates TGF-β,
and contributes to tumorigenesis and tumor progression
[66]. Dierent cancers have been associated with αvβ6,
notably pancreas (100%), ovary (100%), oral (80–100%),
colon (34–37%), and colon metastasize to the liver (71%)
[67]. Besides the αvβ6-targeting monopeptide ­ [
177
Lu]
Lu-DOTA-ABM-5G in clinical trials along with its imag-
ing counterpart ­ [
68
Ga]Ga-DOTA-5G, several αvβ6-targeting
agents labeled with dierent radionuclides are under devel-
opment. One is the radiotheranostic pair ­ [
68
Ga]Ga/[
177
Lu]
Lu-trivehexin, developed by TRIMPT GmbH [60]. Trive-
hexin is a synthesized αvβ6-targeting trimerized peptide
with increased anity compared to monomeric peptides
[68]. While ­ [
177
Lu]Lu-trivehexin is still under preclinical
development, its imaging counterpart ­ [
68
Ga]Ga-trivehexin
has entered clinical trials. In a single-center phase II trial
comparing ­[
68
Ga]Ga-trivehexin and ­ [
18
F]FDG in pancreatic
ductal adenocarcinoma (PDAC) and head and neck squa-
mous carcinoma (HNSCC), ­ [
68
Ga]Ga-trivehexin showed
good uptake, especially along tumor margins, in 24 out of 29
patients [69]. TRIMT GmbH is also developing TRT agents
targeting αvβ8, another tumor-expressing integrin that is
highly homologous to αvβ6 [70]. In addition, an αvβ3-
targeting peptide (EBRGD) labeled with
177
Lu or
225
Ac
for therapy and
64
Cu for imaging is under development by

10. 2694 European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
Table3   Preclinical assets for targets other than SSTR and PSMA
MTC medullary thyroid cancer, NET neuroendocrine tumor, GIST gastrointestinal stromal tumors, CRC colorectal cancer, SCLC small-cell lung
cancer, ccRCC: clear-cell renal cell carcinoma, LCNEC large cell neuroendocrine carcinoma, TNBC triple-negative breast cancer, NSCLC non-
small cell lung cancer
Company Asset Target RadionuclideCarrier classIndications Stage
C-Biomex [44] CBT-001 CAIX
177
Lu Peptide Kidney Preclinical
CBT-004 FAP-α UndisclosedPeptide Solid tumors Discovery
CIS Pharma [45] Undisclosed L1CAM
177
Lu Antibody Multiple cancers Undisclosed
Radionetics [46] Undisclosed GPCRs UndisclosedUndisclosed Undisclosed Undisclosed
Starget Pharma [47] Undisclosed CCK2R
177
Lu Undisclosed MTC, NET, GIST, ovar-
ian, CRC
Lead optimization
Undisclosed GRPR
177
Lu Undisclosed Breast, lung, prostate,
GIST
Lead optimization
Telix Pharmaceuticals
[48]
TLX300 PDGFRa UndisclosedAntibody Sarcoma Discovery
Evergreen Theragnostics
[49]
177Lu-EVG321 CCK2R
177
Lu Peptide SCLC Preclinical
RadioPharm Theranostics
[50]
RAD202 HER2
177
Lu Nanobody Breast, gastric Preclinical completed,
phase I expected in
2024
RV01 B7H3
177
Lu Antibody Prostate, liver, pancreas,
colon cancer
Preclinical
Y-mAbs Therapeutics
[51]
HER2-SADA HER2 UndisclosedAntibody Undisclosed Preclinical, IND expected
in 2025
B7H3-SADA B7H3 UndisclosedAntibody Undisclosed Preclinical, IND expected
in 2025
Bristol Myers
Squibb (RayzeBio) [52]
RYZ801 GPC3
225
Ac Peptide Hepatocellular carcinomaIND enabling
Undisclosed CAIX UndisclosedSmall moleculeccRCC IND enabling
Alpha-9 Oncology [53] Undisclosed MC1R
225
Ac Undisclosed Metastatic melanomaPreclinical
Abdera Therapeutics [54] ABD-147 DLL3
225
Ac Antibody SCLC, LCNEC IND clearance, Phase
I expected in 2024,
FDA fast-tracked on
07/16/2024
ITM Radiopharma [55] ITM-51 FRα
177
Lu Undisclosed Ovarian, adenocarcinomaPreclinical
ITM-52 FRα
225
Ac Undisclosed Ovarian, adenocarcinomaPreclinical
ITM-41 FAP
177
Lu Undisclosed Osteosarcoma, bone metsPreclinical
GlyTherix Ltd [56]
177
Lu-Miltuximab GPC-1
177
Lu Antibody Solid tumors Preclinical
Orano Med [57] DARPin-DLL3 DLL3
212
Pb DARPins SCLC Lead optimization
212
Pb-PRRT (multiple)Undisclosed
212
Pb Undisclosed Undisclosed Discovery
212
Pb-TAT (multiple)Undisclosed
212
Pb Undisclosed Undisclosed Discovery
Ratio Therapeutics [58] FAP-Rx FAP UndisclosedUndisclosed Undisclosed Preclinical, IND expected
in Q4 2024
Atonco [59] ATO-101 (
211
At-
TLX-250)
CAIX
211
At Antibody Bladder cancer Preclinical, Phase I/II
expected in 2024
211
At-Antibody Undisclosed
211
At Antibody TNBC Lead optimization
TRIMT GmbH [60] Undisclosed αvβ6 Multiple Peptide Multiple Discovery
Undisclosed αvβ8 Multiple Peptide Multiple Discovery
NUVIEW [61] NV VPAC1 GRPR
67
Cu Peptide Solid tumors Preclinical, Phase I com-
pleted for 64Cu coun-
terpart, NCT02603965
ArtBio [62] ABA Multiple
212
Pb Undisclosed Solid tumors Lead optimization
ABB Multiple
212
Pb Undisclosed Solid tumors Lead optimization
ABC Multiple
212
Pb Undisclosed Solid tumors Discovery
Bicycle therapeutics [63]
212
Pb-BCY20603 MT1-MMP
212
Pb Peptide Breast, gastric, NSCLCPreclinical

11. 2695European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
EvaThera Theranostics for the treatment of glioblastoma and
non-small cell lung cancer (NSCLC) [71].
GRPR and several other GPCRs are under investigation
for radiotheranostics due to their aberrant expression in mul-
tiple cancers. Besides TRT agents seen in clinical trials, a
few other radiopeptide analogs of GRPR are in preclinical
development (Supplementary Table S2). Another GPCR of
interest is the cholecystokinin-2 receptor (CCK2R), a recep-
tor for gastrin and cholecystokinin that is overexpressed in a
diverse range of solid cancers, notably stromal ovarian can-
cer (100%), SCLC (89%), and astrocytoma (65%) [72]. Like
GRPR, CCK2R-targeting probes are often gastrin analogs
with synthetic modications [73]. Evergreen Theragnostics’
asset EVG321 labeled with
68
Ga/
177
Lu is a radiotheranostic
pair with minigastrin analog targeting CCK2R [49]. In a
previous study in a patient with ES-SCLC, the imaging com-
ponent ­[
68
Ga]Ga-DOTA-MGS5 detected lesions that ­ [
18
F]
FDG did not pick up, indicating the potential of these paired
agents in lung cancer detection and treatment [74]. A few
other CCK2R-based TRT agents are still under early-stage
development, mainly using peptide analogs with agonistic
properties [75]. However, similar to GRPR, an increasing
number of CCK2R antagonists are under investigation, as
antagonists often show better metabolic stability and create
fewer side eects [73].
For CAIX, a few antibodies have been developed against
this target, with most showing high antibody-dependent cel-
lular cytotoxicity (ADCC) in patients [76]. Most recently,
a phase III trial evaluating the CAIX-directed chimeric
IgG1 mAb girentuximab was suspended due to slow body
clearance and low ecacy [77]. Because of their large size,
antibodies have a limited rate of extravasation, restrained
movement in the extracellular matrix, and slow distributive
removal from the interstitial space [78]. As a result, anti-
body doses high enough to be eective for therapy can cause
ADCC on- and o-tumor, limiting the therapeutic windows
of some antibodies [77].
Even though girentuximab failed as a naked antibody, it
has been repurposed for radiotheranostics since the phar-
macodynamics of this strategy is more payload-dependent,
hence lowering the antibody dosage being administered and
widening the therapeutic window [79]. TLX250 ­ ([
89
Zr]Zr-
DFO-/[
177
Lu]Lu-DOTA-girentuximab) is Telix’s investiga-
tional radiotheranostic pair that is currently being evaluated
in clear cell renal cancer, kidney cancer, and other CAIX-
expressing solid tumors. All three active trials are combina-
tion therapies with other anti-cancer agents to deepen drug
eects, reduce antibody dosage, and provide patients with
multiple opportunities to respond. Another girentuximab-
based TRT agent yielded from a collaboration between Telix
and Atonco is ATO-101, an
211
At-labeled girentuximab, with
phase I/II trial in bladder cancer expected to commence in
2024 [59]. Other notable TRT agents in preclinical develop-
ment include CBT-001, a CAIX-targeting peptide developed
by C-Biomex and MD Anderson Cancer Center [44], and a
CAIX-targeting small molecule developed by Bristol Myers
Squibb's RayzeBio [52], both with new radionuclide carrier
as workarounds for the slow clearance issue.
Next is delta-like ligand 3 (DLL3), a Notch-pathway
ligand implicated in promoting growth and establishing
metastatic and resistant phenotypes in SCLC and other neu-
roendocrine tumors [80]. Several DLL3-targeting therapies
are being developed, including antibody-drug conjugates
(ADCs), T-cell engagers, and chimeric antigen receptors
[80]. Notably, the DLL3-targeting ADC Rova-T faced simi-
lar toxicity problems that other ADCs have encountered in
the clinic, where treatment was discontinued due to a high
incidence of adverse events, including thrombocytopenia,
pleural eusion, photosensitivity reactions, and anemia,
despite a good ecacy prole [81]. As these adverse events
were predominantly attributed to the pyrrolobenzodiazepine
toxin warhead [80], the antibody component, SC16.56, could
be repurposed for radiotheranostics. A rst-in-human trial of
­[
89
Zr]Zr-DFO-SC16.56 showed that DLL3 imaging is safe
and feasible [82], while preclinical assessment of its thera-
peutic counterpart ­ [
177
Lu]Lu-DTPA-SC16.56 demonstrated
encouraging ecacy [83]. Abdera Therapeutics’ lead com-
pound ABD-147, an
225
Ac-labeled DLL3 antibody, received
IND clearance in May 2024 to start phase I trial for SCLC
and large cell neuroendocrine carcinoma [84]. Moreover,
Orano Med is optimizing a
212
Pb-labeled DLL3-targeting
antibody-mimetic protein using their designed ankyrin
repeat proteins (DARPins) platform, a new class of custom-
built protein drugs [57].
Like the stories of CAIX and DLL3, other attractive tar-
gets in the ADC space are also under investigation in radio-
theranostics; a few notable examples include HER2, B7H3,
CD38, and multiple other CD markers. Two HER2-targeting
rhenium-188- (
188
Re) or
131
I-labeled nanobodies are cur-
rently in clinical trials (NCT04674722, NCT05982626),
and one
177
Lu-labeled nanobody developed by RadioPharm
Theranostics was set to enter phase I trial in 2024 [50]. For
B7H3, the TRT agent
131
I-Omburtamab failed after a phase
I/II trial for neuroblastoma due to low uptake [85]. RadioP -
harm Theranostics is developing a new anti-B7H3 mono-
clonal antibody labeled with
177
Lu for which the preclinical
package is set to be completed in late 2024 [50]. For CD38,
225
Ac- and
89
Zr/
177
Lu-labeled agents and ADCs using the
same antibody, daratumumab, are currently being developed
in parallel [86– 88]. Many other targets not mentioned here

12. 2696 European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
are included in Supplemental Figure S2 (clinical trials) and
Supplementary Table S2 (preclinical development).
Next‑generation carriers: biologics versus small
molecules/peptides
Radionuclides can be conjugated into many target-binding
moieties, including small molecule agonists or antagonists,
peptides or peptidomimetics, and antibodies or nanobodies.
Structures of three approved TRT agents are examples of
three major classes of radiotheranostic carriers (Fig. 3A).
­[
177
Lu]Lu-DOTATATE is an eight-amino acid-long peptide
agonist covalently connected to the tetraxetan (DOTA) che-
lator. ­[
177
Lu]Lu-PSMA-617 is a small molecule inhibitor
connected to DOTA via a linker. ­ [
90
Y]Y-ibritumomab tiux-
etan (Zevalin) is a murine IgG1 anti-CD20 mAb linked to a
diethylenetriaminepentaacetic acid (DTPA) chelator, which
can chelate to
111
In for imaging.
[
90
Y]Y-ibritumomab tiuxetan was one of the rst radiola-
beled antibodies approved for clinical use in cancer therapy.
Despite proven ecacy as well as therapeutic index and
QOL benet in treating relapsed or refractory low-grade,
follicular non-Hodgkin lymphoma, its clinical adoption
was hindered by several challenges, including the avail-
ability of non-radioactive alternatives, logistical barriers
between nuclear medicine and oncology clinics, and medi-
cal reimbursement issues [90, 91]. Eorts have been made to
overcome logistical barriers involving radiopharmaceutical
Fig.3  Current and next-generation radiotheranostic agents. A)
Approved agents represent three major carrier classes of radiothera-
nostics – small molecule, peptide, and antibody. B) Examples of next-
generation carriers: bispecic antibody, Fab fragment, heterodimeric
peptide, and bicyclic peptide. C) Examples of radiohybrid systems.
Red: Therapy moieties, blue: targeting moieties, green: imaging moi-
eties, black: linkers. The exact structure of ­ [
212
Pb]Pb-BCY20603 is
undisclosed and was derived from the structure of MT1-MMP-target-
ing bicyclic peptide-drug conjugate BT1718 from the same company
[89]

13. 2697European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
therapy by simplifying treatment procedures [91], build-
ing multidisciplinary tumor boards [92], and establish-
ing theranostics Center of Excellence network [93, 94].
A reimbursement support, co-pay assistance, and patient
assistance program was made available to facilitate access
to ­[
90
Y]Y-ibritumomab tiuxetan for both physicians and
patients [91]. The limited clinical usage of ­ [
90
Y]Y-ibritu-
momab tiuxetan also underscores the importance of careful
strategic planning on selecting appropriate disease target,
radionuclide, carrier, etc. when designing radiotheranostics
agents by considering how the radiotheranostics pair can be
integrated into the treatment algorithm of the target disease.
As the eld continues to innovate, these next-generation
carriers are expected to further enhance the clinical poten-
tial of radiotheranostics. The limited eectiveness of ­ [
90
Y]
Y-ibritumomab tiuxetan in other hematological malignan-
cies also hampered the widespread clinical usage of this
drug. The short-lived response and hematologic toxicity
including marrow aplasia, thrombocytopenia, and neutro-
penia have been reported in chronic lymphocytic leukemia
and small lymphocytic lymphoma [95, 96], which can be
attributed to long circulation times leading to increased o-
target toxicity, diculties in delivering sucient doses to
tumors with limited CD20 expression, and immunogenic-
ity related to murine antibody frameworks [96]. In con-
trast, next-generation carriers such as peptides, nanobodies,
and antibody fragments have shown signicant promise in
addressing these issues. Peptides like ­ [
177
Lu]Lu-DOTA-
TATE oer faster pharmacokinetics, enabling more precise
tumor targeting with reduced o-target radiation exposure.
Similarly, antibody fragments provide high target specicity
while maintaining rapid clearance, making them ideal for
applications requiring high precision and minimal toxicity.
The evolution toward smaller, faster-clearing carriers while
maintaining high specicity represents a key advancement
in radiotheranostics, improving ecacy and reducing side
eects compared to early strategies.
Biologics
Antibodies and antibody derivatives represent a large class
of radiotheranostic carriers. The development of antibody-
based radiotheranostics is enabled by the gradual incorpo-
ration of immunotherapy in oncology, the improvement in
antibody technology, and the growing ADC eld [3]. Sev-
eral radioimmunoconjugates (RICs) are in clinical trials, and
many more are currently in preclinical development [97];
a few of them are described above. Most RICs in trials are
monoclonal IgG antibodies, but a few RICs in early clini-
cal development belong to other antibody classes, including
bispecic antibodies, Fab domains, and nanobodies.
Bispecific antibodies (bsAbs) represent an emerging
antibody class with unique modes of action targeting two
separate epitopes. Compared to monospecic antibodies,
this class of antibodies has superior inhibition and higher
tumor specicity [98]. FPI-2068 is an
225
Ac-labeled bsAb
developed by Fusion Pharmaceuticals and AstraZeneca to
target tumors expressing either or both EGFR and c-MET
(Fig. 3B) currently in a phase I open-label dose escalation
study [99]. Preclinical data from a recent study in lung and
colorectal xenograft models treated with a single dose of
FPI-2068 showed sustained tumor regression (>  28 days)
[100]. At this time, no other full-size bsAb RIC was seen in
clinical trials or publicly available pipelines.
One major disadvantage of full-length antibodies is that
their relatively high molecular weights lead to slow diusion
and clearance times, especially in solid tumors. The biologi-
cal half-lives of IgG1 antibodies range from 14 to 21 days
[97], longer than half-lives of many medical radionuclides.
Thus, a signicant portion of these radionuclides will decay
while the antibody is still in circulation and radiosensitive
organs will be exposed to unnecessary radiation. Immuno-
globin-derived antigen-binding fragments are therefore of
interest due to faster clearance. Fab domains (~  50 kDa) have
plasma half-lives of 30 min, while single-chain variable frag-
ments (scFv;  ~ 25 kDa) have half-lives of only 10 min [101].
A study showed that
68
Ga-labeled nanobodies (~  15 kDa)
had 90% blood clearance only an hour post-injection [102].
Moreover, fragments are more advantageous than full-size
antibodies regarding their low immunogenicity, high tissue
penetration, relative ease of production, and potential to
cross the blood–brain barrier [103 ]. Their small molecular
weights also bring disadvantages, most signicantly rapid
degradation, high kidney uptake, and half-lives too short
for therapeutic purposes [104]. For radiotheranostics, anti-
body fragments are often structurally modied to extend
their half-lives, usually by conjugation to proteins such as
albumin or by PEGylation [105].
Fab domain was the rst and so far most successful anti-
body fragment format, accounting for almost half of all
antibody fragments entering clinical trials [103]. However,
its footprint in radiotheranostics is limited, as only one Fab-
based agent was found within clinical trials or preclinical
pipelines. LuCaFab, or ­ [
177
Lu]Lu-CHX-A″ -DTPA-6A10,
(Fig. 3B) is a
177
Lu-labeled Fab fragment targeting carbonic
anhydrase XII (CAXII) developed by Helmholtz Munich
that entered phase I trial (NCT05533242) for dosimetry and
toxicity in 2023. Preclinical studies in a glioblastoma xeno-
graft mouse model show stability under physiological condi-
tions, signicant tumor accumulation (3.1%ID/g) 3 h after
systemic injection, but inability to cross the blood–brain
barrier [106]. This TRT agent is therefore injected into the
resection cavity of patients who underwent surgical excision
of their glioblastoma and is considered maintenance therapy.
Initial clinical data in three patients show no or low leakage
into other cerebral compartments, good tumor uptake in the

14. 2698 European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
resection cavity, and no extracerebral adverse eects in the
kidney or bone marrow [107].
A nanobody, containing only the variable antigen-tar-
geting domain of the heavy chain, can retain the binding
anity of conventional antibodies and can also form n-
ger-like structures to recognize cavities or hidden epitopes
[108]. However, their rapid clearance from blood reduces
their plasma concentration and brain concentration. Their
smaller molecular size also causes high kidney accumula-
tion, leading to unwanted renal toxicity [109]. These limi-
tations render nanobodies as radiotherapeutic carriers less
feasible at the current time. Several strategies to extend
circulation time for nanobodies and other Fragments can
enhance antitumor ecacy [110 , 111]. Currently, a few
clinical radiolabeled nanobodies are designed to target solid
cancers. A PD-L1-targeting nanobody developed by RadioP-
harm Theranostics, ­ [
177
Lu]Lu-RAD204, is in a phase I trial
(NCT06305962) for metastatic NSCLC. The rst patient
was dosed with ­ [
177
Lu]Lu-RAD204 in July 2024 [112].
The technetium-99 m- labeled imaging component ­ [
99m
Tc]
Tc-NM-01 demonstrated no drug-related adverse reactions
and good tumor-to-background contrast 2 h after administra-
tion in a previous open-label, nonrandomized phase I study
(NCT02978196) in 16 patients with untreated NSCLC [113].
As mentioned above, RadioPharm Theranostics has another
nanobody targeting HER2 in breast and gastric cancer that
is expected to enter clinical trials in 2024. CIS Pharma also
has multiple undisclosed nanobody-radionuclide conjugates
in development [45].
Another interesting TRT agent is GD2-SADA:
177
Lu-
DOTA, a two-step pretargeted approach that harnesses
the Self-Assembling and DisAssembling (SADA)-bsAb
platform [114] to target disialoganglioside (GD2) in neu-
roectodermal tumor [115, 116]. The platform consists of a
SADA domain fused to an anti-GD2 × anti-DOTA bispecic
scFv. The SADA domain can assemble into stable tetramers
for strong tumor binding and disassemble into dimers and
monomers (~  50 kDa) for quick clearance [114]. With this
platform, the SADA-bsAb fusion binds to the tumor target
rst. Then, ­ [
177
Lu]Lu-DOTA is administered, binding to the
anti-DOTA domain of the bsAb. Unbound SADA-bsAb mol-
ecules then disassemble and clear via the kidney [117]. This
methodology is designed to lower the time radionuclides
travel in the body and thus create less o-tumor cytotoxic-
ity. In a preclinical study, this two-step platform was shown
to deliver large doses of radiation (1.48 MBq/kg for
225
Ac
and 6,660 MBq/kg for
177
Lu) to tumors in multiple mouse
models without any toxicities to the bone marrow, liver, kid-
neys, spleen, or brain [114]. Besides the clinical asset GD2-
SADA:
177
Lu-DOTA in trial (NCT05130255), Y-mAbs Ther-
apeutics is developing other SADA platforms, one targeting
CD38 that entered a trial (NCT05994157) for relapsed or
refractory non-Hodgkin lymphoma, and two targeting HER2
or B7H3, with IND lings expected in 2024 and 2025 [51].
Another emerging radiotheranostic carrier is Designed
Ankyrin Repeat Proteins (DARPin), a class of antibody-
mimetic proteins that combine superior characteristics of
short circulatory half-lives in the range of hours, high stabil-
ity due to the lack of disulde bonds, and antibody-like bind-
ing anity due to enlarged binding surface [118]. Several
radio-DARPin therapeutics are under development, includ-
ing the
212
Pb-labeled DLL3-targeting DARPin mentioned
above, and
177
Lu-labeled HER2-targeting DARPin G3 [119].
Despite promising mechanisms of action and good preclini-
cal data, no DARPin or antibody-derived fragments are yet
approved for cancer treatment or in late-phase clinical stud-
ies, suggesting that these classes of immuno-oncology drugs
need further research and development.
Small molecules/peptides
While small molecules and peptides have lower anity and
shorter circulatory half-lives than antibodies, they demon-
strate higher eciency in tissue penetration and cell inter-
nalization [120]. The shift from agonists to antagonists
represents a major change in next-generation radioligands,
and we also see multiple new synthetic methods to modify
peptide structures in preclinical assets. Heterodimerized
peptides and bicyclic peptides are commonly seen strate-
gies to increase the anity and specicity of these smaller
radiotheranostic carriers.
For CCK2R-, GRPR-, and other GPCR-targeting radio-
theranostics, problems arise as TRT agents often have low
enzymatic stability and can lead to multiple side eects
because of their agonistic biological effects [73, 121].
Though antagonistic peptides were previously less preferred
because they are unlikely to internalize, evidence from
multiple peptide receptors suggests that the use of recep-
tor antagonists appears to have improved pharmacokinetic
properties and a better safety prole, potentially due to their
ability to bind more target sites or multiple receptor variants
[122]. Indeed, head-to-head comparisons showed that the
SSTR antagonist ­ [
177
Lu]Lu-DOTA-JR11 performed better
than the SSTR agonist ­ [
177
Lu]Lu-DOTATOC in a clinical
trial, with 2.9 (2.0–4.8) times higher median tumor-to-
kidney absorbed-dose ratio [123]. The GRPR antagonist
­[
111
In]In-SB9 also performed better than a GRPR agonist
in a prostate cancer in vivo model, showing faster back-
ground clearance and comparable tumor uptake despite
no detectable internalization in prostate cancer PC3 cells
[124]. Radiolabeled GRPR antagonist ­ [
177
Lu]Lu-NeoB
showed high GRPR binding anity, high tumor uptake

15. 2699European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
eciency, and high in vivo metabolic stability in a preclini-
cal study, and is currently in early-phase trials for multiple
indications (NCT06247995, NCT03872778, NCT05739942,
NCT06379217) [73, 121].
Similar to bsAbs, heterodimeric radioligands increase
targeting ecacy and specicity by binding two dier-
ent targets [125]. For prostate cancer, the GRPR  × PSMA
bispecic heterodimer ­ [
68
Ga]Ga-iPSMA-Lys
3
-Bombesin
(Fig. 3B) was synthesized by combining a PSMA-targeting
motif with a bombesin-based antagonist, which showed high
tumor uptake and fast blood clearance [126]. This heterodi-
mer radioligand is the rst and only GRPR  × PSMA bispe-
cic peptide that has been clinically evaluated, though only
in four healthy volunteers and one prostate cancer patient.
However, many others have been synthesized and investi-
gated in preclinical models of prostate cancers [127, 128].
Moreover, recent works on heterodimeric radioligands tar-
geting the integrin αvβ3 combined with SSTR2 for liver met
NETs (NCT06632873), MC1R for melanoma [129], VEGF2
for glioma [130], or EGFR for pancreatic cancer [131] have
shown promising imaging and therapeutic capacities.
Bicyclic peptides are excellent targeting probes as they
possess antibody-like anity and selectivity, small mole-
cule-like synthesis, good proteolytic stability, and high mem-
brane permeability [132]. In 2023, a
18
F-labeled bicyclic
peptide targeting EphA2 was shown to visualize PSMA-
negative prostate cancer in high contrast with binding an-
ity in the nanomolar range [133]. In 2019, a bicyclic peptide
targeting matrix metalloproteinase MT1-MMP labeled with
68
Ga and
177
Lu was reported to have subnanomolar an-
ity to human and mouse MT1-MMP, rapid accumulation
in tumors, and fast background clearance [134]. ­[
212
Pb]Pb-
BCY20603 (Fig. 3B) is a bicyclic peptide targeting MT1-
MMP for treating breast, gastric, and NSCLC developed by
Bicycle Therapeutics and Orano Med. A 2023 report showed
that ­[
212
Pb]Pb-BCY20603 has better tumor accumulation
than a
212
Pb-labelled MT1-MMP-targeting antibody in a
mouse xenograft model [135]. This radiotherapy agent is
estimated to be over 1,000 times more potent than a compar-
ator peptide-toxin conjugate [135]. Although no radiolabeled
bicyclic peptide is currently in clinical development, this
class of carriers holds excellent promise for radiotheranostic
applications.
In summary, radiolabeled antibodies and antibody frag-
ments represent an important class of radiotheranostic car-
riers with numerous agents under clinical assessment and
preclinical development. Translation of most prospective
agents is challenging, as large intact antibodies have slow
pharmacokinetics and poor penetration, while small frag-
ments have low stability and high o-tumor accumulation
Fig.4  General advantages and
disadvantages of dierent radio-
nuclide carriers. Created with
BioRender.com

16. 2700 European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
(Fig. 4). Pre-targeting strategies and improvement in anti-
body engineering are trying to overcome these problems, as
noted in some assets described above. Even with limited evi-
dence, the development of stable and specic novel peptide
carriers such as heterodimers and cyclic peptides indicates
the great potential of radioligands for cancer therapy. The
development and application of some new radiotheranostic
carriers, including nucleic acid aptamers, peptidomimetic
small molecules, lipid nanoparticles, as well as carrier sys-
tems with higher radionuclide load, are still in their infancy,
some of which were recently reviewed by Zhang et al. [136].
Next‑generation radionuclides: Challenges
and emerging trends
The development of next-generation radionuclides is at the
forefront of advancing radiotheranostics, addressing the
growing need for more eective, versatile, and accessible
radiopharmaceuticals. As the field continues to evolve,
the selection of radionuclides for therapy has expanded to
include alpha- and beta-emitters with distinct properties
tailored to specic clinical applications. However, several
challenges remain, including radionuclide production limita-
tions, pairing mismatched imaging and therapeutic radionu-
clides, and the complexities of chelation chemistry.
Alpha‑ versus beta‑emitters
Designing radiotheranostic agents involves matching the
carrier molecule to a radionuclide with similar physical and
physiochemical properties. Carrier-radionuclide matching
depends mainly on circulation time. For example,
225
Ac is
best suited for slow circulating carriers due to its long half-
life of 9.92 days, while
211
At should be paired with small
molecules, peptides, or antibody fragments due to its short
half-life of 7.21 h. Besides carrier-radionuclide matching,
indication-radionuclide matching, and diagnostic-thera-
peutic radionuclide pairing should also be considered when
developing radiotheranostic agents.
For therapeutic radionuclides, the choice between α
and β
−
emitters is fundamentally a trade-o between the
number of particles necessary to cause clinically relevant
damage versus the spread of energy within tumor masses
[8]. Multiple β
−
-particles are needed to kill one cell, but
bombardment of adjacent cells can enhance the killing
of non-antigen-expressing cells via crossre eects, par-
tially compensating for tumor heterogeneity [25]. Fewer
α-particles are required to kill individual cancer cells
because of their high LET, and the short pathlengths of
α emitters mean they are better at sparing non-targeted
cells [25]. Consequentially, β
−
emitters are best tted for
heterogeneous tumors, while α-emitters are better than
β
−
emitters at treating liquid cancers, micrometastases,
minimal-residual diseases, and homogenous tumors. How-
ever, recent evidence suggested that α-emitters can kill
non-antigen-expressing cancer cells via bystander eects,
potentially by p53-mediated transfer of genomic instability,
increased level of reactive oxygen species in the TME, or
adaptive antitumoral immune response [137]. These eects
make α-emitters more eective in challenging cancer with
diverse antigen expressions. The minimal o-tumor toxic-
ity and higher radiation energy explains, combining with
the potential to treat patients with heterogenous antigen
expression explain why targeted alpha therapy has recently
attracted more interest in radiotheranostics.
Although having only three active clinical trials,
211
At
is widely regarded as one of the most promising α-emitters
for targeted radiotherapy due to several unique advantages.
Its intermediate half-life of 7.2 h is ideal for short-circu-
lating carriers such as small molecules, peptides, and anti-
body fragments, allowing just enough time for preparation,
administration, and tumor targeting while minimizing o-
target radiation exposure. Unlike other α-emitters such as
225
Ac or
212
Pb, which undergo complex decay cascades
emitting multiple α and β
−
particles,
211
At has a straightfor-
ward decay scheme, producing a single high-energy α par-
ticle [138]. This property reduces collateral radiation dam-
age to surrounding healthy tissues, making it particularly
well-suited for precision radiotherapy in small, localized
tumors or micrometastases. Additionally,
211
At benets
from a cost-eective and scalable production process. It
is produced via cyclotron irradiation of the widely avail-
able and inexpensive material bismuth-209 (
209
Bi) [138].
This straightforward production method oers a signicant
advantage over other α-emitters such as
225
Ac, which rely
on limited global supplies from thorium-229 (
229
Th) decay
or energy-intensive irradiation of radium-226 (
226
Ra). The
simpler production pathway for
211
At not only reduces
costs but also has the potential to increase availability,
addressing one of the major bottlenecks in α-emitter-based
therapies. Challenges in developing
211
At radiopharma-
ceuticals include its unpredictable halogen-like behavior,
its low reactivity, and the instability of astatoaryl bond
that are prone to in vivo deastatination, making it harder
to design biologically stable compounds [138]. Ongoing
research and technological advancements are expected
to expand the clinical utility of
211
At, solidifying its role
as a key player in the next generation of α-emitter-based
radiopharmaceuticals.
Beyond a few α emitters seen in trials, other emerging
radionuclides include terbium-149 (
149
Tb), bismuth-213
(
213
Bi) and thorium-227 (
227
Th). As part of the terbium
isotope family,
149
Tb oers unique properties, including a
half-life of 4.1 h and the ability to emit α particles with high
LET ­(E
α
 = 3.97 MeV, 140 keV/μm) [139]. Its co-emission of
positrons also allows for simultaneous imaging, making it a

17. 2701European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
true theranostic radionuclide.
213
Bi, with its short half-life
of 45.6 min [140], is suited for rapid targeting applications,
while
227
Th, with a longer half-life of 18.7 days [141], is
ideal for slowly circulating carriers like antibodies. These
radionuclides expand the clinical α-emitter portfolio, oer-
ing diverse options to match specic tumor types and thera-
peutic needs, though challenges in production, logistics, and
chelation chemistry remain key obstacles to their clinical
adoption.
Isotopic pairing
Beyond emitter properties, pairing therapeutic radionu-
clides with complementary imaging agents remains a
critical factor for clinical success. Most therapeutic radio-
nuclides emit gamma rays, but their gamma emission is
rather weak, only allowing for monitoring during treat-
ment with limited diagnostic potential [142]. Therefore, a
therapeutic radionuclide is usually coupled with an imag-
ing radionuclide directly bound or chelated to the same
backbone. True radiotheranostic pairs are isotopic radio-
nuclides with the same number of protons and electrons,
which include
64
Cu/
67
Cu,
123,124
I/
131
I,
152,155
Tb/
161
Tb, and
203
Pb/
212
Pb. Paired isotopes with near-identical chemistry
could provide near-identical specicity, biodistribution,
and metabolism of paired imaging-therapy agents, leading
to rising interest in preclinical development [143, 144]. Of
the above-mentioned pairs,
64
Cu/
67
Cu stands out because
the relatively long half-life of
64
Cu ­(t
1.2
 = 12.7 h) provides
a logistical advantage over
18
F and
68
Ga, extended tumor
imaging, and the ability to detect metastatic lesions. This
positron emitter also has a lower positron energy when
compared to
68
Ga, resulting in increased resolution and
imaging quality [145]. Furthermore, even though the
relatively short half-life of
67
Cu limits its usage in large
tumors,
67
Cu is an ideal therapeutic radionuclide for small
tumors as its β
−
emission is slightly higher than
177
Lu. The
development of copper-based radiotheranostics is limited
by a shortage of
67
Cu, but new production methods are
being explored [146, 147].
Two terbium isotopes,
152
Tb and
155
Tb, are potential
imaging counterparts of
161
Tb, although
161
Tb has only been
seen paired with
68
Ga in current clinical trials. The gamma
emitter
155
Tb ­(t
1.2
 = 5.32 days) oers SPECT imaging capa-
bility over an extended period, suitable for peptides and
antibodies; while the positron emitter
152
Tb ­(t
1.2
 = 17.5 h)
is more suitable for fast-circulating radionuclide carriers.
Again, the major limitations of these isotopes are produc-
tion shortage and clinical-grade purity [148]. Lastly, the
isotopic pair
203
Pb/
212
Pb has also gained traction in recent
times due to their fairly optimized production and puri-
cation processes [149]. The imaging component,
203
Pb has
a good imaging prole, while the therapeutic component
212
Pb has a shorter half-life ­ (t
1.2
 = 10.6 h) compared to
225
Ac,
making this pair more suitable for smaller carriers. Yet, the
shorter half-life of
212
Pb poses a challenge for logistics and
transportation, making it dicult for both R&D and clinical
applications.
Radionuclide production
As many medical radionuclides have half-lives in hours to
days, on-site production is often necessary to allow time
for chelation and administration while mitigating loss of
radioactivity. Radionuclides are usually produced in cyclo-
trons or reactors; both of which are expensive to build,
manage, and maintain, adding another logistical challenge
[150]. For example, demand for the promising α emitter
225
Ac is higher than its current supply availability. Actin-
ium-225 is produced via irradiation of
226
Ra or extraction
of
229
Th decay products, both in non-GMP settings and
from a limited number of non-centralized suppliers [18].
Shortage of quality-controlled, clinical-grade
225
Ac forced
Bristol Myers Squibb to halt patient enrollment into their
ACTION-1 phase III study testing ­ [
225
Ac]Ac-DOTATATE
for a few months in 2024 [151]. Besides therapeutic radio-
nuclides with approved medical usage-
177
Lu,
131
I, and
90
Y, clinical-grade production of other radionuclides has
not been well developed and optimized. This is the major
limiting factor for many radionuclides with high poten-
tials, such as
149
Tb or several scandium and lanthanum
isotopes suitable for match-pair applications [152]. Even
in the case of
177
Lu, increased interest in this radionuclide
has created a supply shortage that requires an immediate
solution.
To solve shortage problems, the last decade has seen
a multitude of global eorts to develop new schemes of
production, separation methods, and reactor technology
by the research community, private companies, and pub-
lic agencies [153]. Research and commercial reactors are
actively being built to address radionuclide demands. The
Bruce nuclear power plant in Ontario, Canada became the
rst commercial nuclear reactor to produce medical grade
177
Lu in September 2022, intending to meet global sup-
ply needs of this critical radionuclide until 2064 [154].
Expansion of the University of Missouri nuclear reactor
(MURR), the only producer in the US for multiple medi-
cal radioisotopes, was scheduled to be completed in the
Fall of 2024 [155]. Partnerships between pharmaceutical
companies and radioisotope producers including recent
deals in 2024 between Bayer and PanTera [156], Molecu-
lar Partners and Orano Med [157], ARTBIO and Nucleus
RadioPharma [158], or Provision Diagnostic and Ionetix
[159], in addition to the participation of big conglomerates
like General Electric in the supply chain, are expected to
help boost production.

18. 2702 European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
Chelation chemistry
The development of radiotheranostic agents depends
not only on selecting appropriate radionuclides but also
on ensuring their stability and compatibility through
effective chelation chemistry. Chelators are critical for
securely binding radionuclides to carrier molecules, pre-
serving their biodistribution, and minimizing off-target
effects. However, designing imaging counterparts for
therapeutic radionuclides without isotopic pairs presents
significant challenges due to differences in decay prop-
erties, chemical behaviors, and biodistribution. Both
approved
177
Lu agents are paired with
68
Ga, a positron-
emitting radionuclide with a half-life of 67.8 min. This
pairing is commonly seen in labeling small molecules or
peptides, while
89
Zr is more widely used to label anti-
bodies because of a more suitable half-life of 3.27 days,
despite the different chelation chemistry of zirconium
compared to lutetium [160]. Lutetium-177 has also been
paired with
99m
Tc,
18
F, and
67
Cu [161– 164]. Actinium-225
is often paired with
111
In or
89
Zr for long half-life car-
riers, and
68
Ga or
64
Cu for short half-life carriers (for
example, NCT05363111, NCT03746431, NCT03746431).
However, the chemical properties and behaviors of some
common imaging radionuclides with small radii differ
from radionuclides with large radii like
225
Ac,
177
Lu, or
other elements of the lanthanide and actinide series [165].
Understanding these complexities is vital for optimizing
radiotheranostic design and improving both imaging and
therapeutic efficacy.
The dierences in the behaviors of paired radionuclides
can lead to dierences in dosimetry estimation from imag-
ing and actual therapeutic dosimetry. The
68
Ga/
177
Lu pairing
was shown to be highly compatible [166, 167], but mis-
match biodistribution was seen in
89
Zr/
177
Lu due to dif-
ferent chelation chemistry, while mismatch half-life and
mismatch chelation chemistry are problems for
68
Ga/
225
Ac
and
89
Zr/
225
Ac, respectively [168]. Dierences in chela-
tion chemistry are major causes for the mismatch stability
of imaging/therapy radionuclides. The stable macrocyclic
DOTA can chelate elements in  + 3 oxidation state, includ-
ing Ga, Y, Lu, Tb, In, and Ac, making it one of the most
used chelators [169]. Yet, dierent DOTA complexes have
dierent stability due to size and formation/disassociation
kinetics [170]. ­Zr
4+
-DOTA complex is less stable, and the
chelation reaction happening at high temperatures is not
suitable for antibodies, so DFO is usually used to label
89
Zr
instead [171].
Furthermore, radiation emitted from the decay of radio-
nuclides can attack their chelators, leading to radiolytic deg-
radation that compromises stability [172]. Dierent radio-
nuclides have dierent decay chains, producing daughter
isotopes with distinct radioactivity. After decay, radioactive
daughter isotopes could be released from the chelation
complex and be free to distribute to o-target tissues. This
is especially important for alpha emitters, as their strong
nuclear recoil energy can break chemical bonds and eject
daughter nuclei, and measuring the in vivo redistribution
of these progenies is extremely dicult [173]. Another sig-
nicant issue arises from transmetalation and transchelation
phenomena. Transmetalation occurs when a radionuclide
is replaced by another metal ion, often from endogenous
sources like ­ Ca
2+
, ­Zn
2+
, and ­Fe
3+
. This leads to the decom-
plexation of the radiolabeled carrier and the release of the
radionuclide, which may accumulate in o-target tissues,
resulting in toxicity. The size of the radionuclide and the
stability of the chelation complex influence the rate of
transmetalation [174, 175]. On the other hand, transchela-
tion involves the displacement of a radionuclide from its
chelator by competing ligands, such as endogenous metal-
loproteins or other biological molecules [174]. Examples of
this phenomenon include
89
Zr
4+
by transferrin [176],
225
Ac
3+

by albumin [177], or
64
Cu
3+
by superoxide dismutase [178].
This process occurs when the competing ligand has a high
anity for the radiometal and forms a more stable complex
than the original chelator, and can cause similar issues of
non-specic redistribution of the radionuclide to unintended
tissues [174].
These issues further complicate radionuclide pairing. To
overcome these challenges, it is essential to advance our
understanding of chelation chemistry, decay physics, and
the biological eects of radionuclides. More research is
needed to optimize chelation strategies, mitigate the eects
of radiolytic degradation, and prevent transmetalation and
transchelation, ultimately improving the safety and ecacy
of radiotheranostic agents.
Radiohybrid systems
Radiohybrid systems represent an emerging approach
to pairing imaging-therapy radionuclides with different
chelation chemistry. Radiohybrid systems include two
complexation moieties in the same molecule to label
corresponding imaging or therapeutic radionuclide in an
independent manner (Fig. 3 C). For example, the clinical
stage TRT agent ­ [
177
Lu]Lu-rhPSMA-10.1 is a radiohy-
brid, dual-chelator agent containing a silicon–fluoride
acceptor (SiFA) for
18
F-fluoride labeling and a DOTA
chelator for Lu complexation [179]. For imaging, pos-
itron emitter
18
F and natural
175
Lu are chelated to the
radiohybrid ligand, while stable
19
F and radioactive
177
Lu
are incorporated in the therapeutic agent. The resulting
18
F[F]-rhPSMA-10.1 and ­ [
177
Lu]Lu-rhPSMA-10.1 shared
chemically identical molecules, thus presenting near-
identical biodistribution profiles. As for antibody carri-
ers, a 2024 study reported the first-in-class radiohybrid

19. 2703European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
system for
89
Zr/
177
Lu pairing [180]. This system includes
a DFOB-DOTA adduct separated by a l-lysine residue
attached to a PSMA monoclonal antibody (HuJ591).
This system was shown to have regioselective binding
to
89
Zr and
177
Lu where DFOB favorably binds to
89
Zr
and DOTA favorably binds to
177
Lu. Agents chelated with
either
89
Zr or
177
Lu showed no significant difference in
tumor accumulation and ex vivo distribution, making it a
good chelator for
89
Zr/
177
Lu pairing. The significance of
this DFOB-DOTA adduct goes beyond
89
Zr/
177
Lu pairing,
as DOTA can chelate other radionuclides. Isostructural
pairing allows for more accurate dosimetry prediction,
making this strategy a great alternative to conventional
designs of radiotheranostic agents.
In summary, the development of next-generation radio-
nuclides for radiotheranostics holds signicant promise,
but overcoming key challenges is essential for their broader
clinical application. Advances in the selection of α- and
β-emitters, along with the exploration of emerging radio-
nuclides, oer exciting potential for more eective and per-
sonalized cancer treatments. However, issues such as radio-
nuclide production limitations, the complexities of isotopic
pairing, and chelation stability must be addressed to ensure
these innovations reach their full clinical potential. Contin-
ued research and technological advancements will be crucial
in rening these approaches and overcoming the current bar-
riers to optimize the safety and ecacy of radiotheranostic
agents.
Concluding remarks and future perspective
Rapid advances in nuclear medicine, molecular imaging, and
multidisciplinary research have signicantly expanded the
frontiers of radiotheranostics. Many novel radiotheranostic
agents are currently under development for a diverse range
of indications, from liquid to solid cancers, with the poten-
tial for applications beyond oncology [181]. However, the
progress of radiotheranostics faces critical challenges, par-
ticularly in the clinical production of radionuclides, limited
workforce, regulatory issues, and implementation barriers.
Regulatory frameworks for radiopharmaceuticals are often
complex and inconsistent across regions, which can slow the
clinical translation of promising new therapies [150].
Eorts are underway to streamline these processes, with a
pressing need for greater harmonization of global regulatory
standards to ensure broader access to these innovative treat-
ments. Initiatives such as the 2023 consultancy meeting held
by the International Atomic Energy Agency are trying to
address the workforce gaps by developing a global training
curriculum and establishing radiotheranostic centers [182].
Regulatory bodies like the FDA and EMA have increas-
ingly shown willingness to approve radioligand therapies
based on strong clinical data, encouraging further innova-
tion within the eld. The increasing collaboration among
industry, academia, and healthcare providers, coupled with
rapid advances in biomedical sciences, drug discovery, and
nuclear physics is reshaping the radiotheranostic landscape.
Preclinical and clinical trials continue to expand the scope
of cancer types that can benet from radiotheranostics,
bringing us closer to a broader, more personalized approach
to oncology. To ensure the continued growth and clinical
impact of radiotheranostics, further investment in research,
technological innovation, and regulatory alignment is essen-
tial. By addressing current barriers, the eld is poised to
revolutionize cancer care, oering more eective and per-
sonalized treatments for patients worldwide.
Abbreviations  ADC: Antibody–Drug Conjugate; ARPIs: Androgen
Receptor Pathway Inhibitors; BFC: Bifunctional Chelator; bsAb: Bispe-
cic Antibody; CAIX: Carbonic Anhydrase IX; CRC : Colorectal Can-
cer; DARPin: Designed Ankyrin Repeat Proteins; DFO : Deferoxamine;
DLL3: Delta-like Ligand 3; DOTA: Tetraazacyclododecanetetraacetic
Acid; DOTATATE/DOTATOC: Derivatives of somatostatin analogs;
EMA: European Medicines Agency; Fab : Antigen-Binding Fragment;
FAP:  Fibroblast Activation Protein; FAPI:  Fibroblast Activation
Protein inhibitor; FDA : U.S. Food and Drug Administration; GEP-
NET: Gastroenteropancreatic Neuroendocrine Tumors; GRPR: Gas-
trin-Releasing Peptide Receptor; IND: Investigational New Drug;
LCNEC: Large Cell Neuroendocrine Carcinoma; mAb: Monoclonal
Antibody; mCRPC: Metastatic Castration-Resistant Prostate Can-
cer; MTC: Medullary Thyroid Cancer; NET: Neuroendocrine Tumor;
NIS: Sodium-Iodine Symporter; NSCLC: Non-Small Cell Lung Cancer;
OS: Overall Survival; PEGylation: Polyethylene Glycol Modication;
PET: Positron Emission Tomography; PFS: Progression-Free Survival;
PSMA: Prostate-Specic Membrane Antigen; RIC: Radioimmunocon-
jugate; SADA: Self-Assembling and DisAssembling; scFv: Single-
Chain Variable Fragment; SOC: Standard of Care; SPECT: Single-Pho-
ton Emission Computed Tomography; SSTR: Somatostatin Receptor;
TAT :  Targeted Alpha Therapy; TME:  Tumor Microenvironment;
TNBC: Triple-Negative Breast Cancer
Supplementary Information  The online version contains supplemen-
tary material available at https:// doi. org/ 10. 1007/ s00259- 025- 07103-7.
Acknowledgements  H.C.M. is a CPRIT Scholar of Cancer Research.
The authors thank Leslie A. Billings, Ryan P. Coll, Zhiwen Liu, and
Cong-Dat Pham of the University of Texas MD Anderson Cancer
Center for editing the manuscript.
Author contributions  Conceptualization: HHT, AY, HCM. Investiga-
tion: HHT, AY. Visualization: HHT, AY. Supervision: HCM. Writing –
original draft: HHT, AY. Writing – review & editing: HHT, AY, HCM.
Funding A.Y. and H.C.M. acknowledge the Cancer Prevention and
Research Institute of Texas (CPRIT) for nancial support.
Data availability  The datasets used and/or analysed during the cur-
rent study are available from the corresponding author on reasonable
request.
Declarations 
Competing interests  Authors declare that they have no competing
interests.

20. 2704 European Journal of Nuclear Medicine and Molecular Imaging (2025) 52:2685–2709
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