Ch5 Radiopharmaceuticals nuclear medicine.pdf

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1. RADIOPHARMACEUTICAL
GUL NAZSHABBIR
BSC MIT( MEDICAL IMAGING TECHNOLOGY)
CHILDREN’S HOSPITAL LAHORE

2. Radiopharmaceuticals –Definition
•Radionuclides are rarely used in simple form.
•Tagged with chemical compounds for better targeting.
•A radiopharmaceutical = radionuclide + chemical compound, suitable for human use.
•Approved by FDA like other drugs.

3. Use of Radiopharmaceuticals
•Mainly for diagnostic imaging, not therapy.
•Administered in tracer doses.
•Produces no pharmacologic effects

4. Radiopharmaceutical Design
•Two major considerations:
1. Radionuclide properties
•2. Biochemical targeting
•Both must be optimized for safety & effectiveness

5. Selection of Radionuclide
•Based on:
•Patient radiation dose minimization.
•Detection compatibility with imaging equipment.
Radiation Dose Minimization
•Use shortest half-life compatible with biological process.
•Shorter half-life = lower dose, faster decay.
•Rule of Thumb:
•Half-life ≈0.693 ×T (T = imaging time post-injection).

6. •Emission Characteristics
•Ideal radionuclide:
•Emits only gamma rays (no beta or electrons).
•Gamma energy: 100–300 keV.
•Monochromatic gamma rays preferred for clarity.
•Energy Considerations
•High energy: better penetration, but less detector interaction.
•Low energy: may be absorbed inside body →poor imaging.
•Must balance penetration with detector efficiency.

7. Ideal Radionuclide –Tc-99m
•Technetium-99m (Tc-99m) ideal because:
•6-hour half-life
•140 keV gamma energy
•No harmful emissions
•Easily available from generator
•Economical and effective

8. Selection of a Chemical in Radiopharmaceuticals
•Must be non-toxic in required amount.
•Should localize in target organ or tissue.
•Must show difference in uptake between normal & diseased tissues.
•Key term: Target-to-Non-Target Ratio
•→Higher ratio = better image contrast.

9. Factors Affecting Chemical Distribution
•Choice guided by pharmacological data.
•Physiochemical factors influence uptake & localization.
•3 key determinants:
•1. Route of administration
•2. Blood flow to organ/tissue
•3. Tissue extraction ability

10. Route of Administration
•Radiopharmaceuticals usually given intravenously (IV).
•IV route = fastest entry into bloodstream.
•Ensures quick distribution to target areas.

11. Role of Blood Flow (Perfusion)
•Blood delivers drug to tissues during first pass (10–20 sec).
•Diseases can reduce perfusion →affect uptake.
•More blood flow = more radiotracer delivery.

12. Plasma Protein Binding
•Drugs bound to plasma proteins stay in blood longer.
•Less localization in tissues.
•Free (unbound) drugs = better tissue uptake.

13. Mechanisms of Tissue Extraction
•Drug uptake via:
•Simple diffusion
•Filtration
•Active transport
•Receptor binding
•Phagocytosis
•These are basis for designing radiopharmaceuticals.

14. Conclusion
•Effective chemical selection depends on:
•Uptake pattern in normal vs diseased tissue.
•Rapid circulation and target localization.
•Pharmacologic behavior of drug.
•Understanding these factors = better imaging agents.

15. Development of Radiopharmaceuticals
•Begins after selecting radionuclide and chemical.
•Involves step-by-step process to ensure effectiveness, safety, and regulatory approval.
•Main stages:
•Chemical studies
•Animal studies
•Clinical trials
•Quality control

16. Chemical Studies
•Aim: establish best method for radiolabeling.
•Determine:
•Labeling conditions
•In vitro stability
•Radiochemical impurities

17. Animal Distribution & Toxicity Studies
•Purpose: assess biodistribution and safety.
•Performed on normal and diseased animals.
•Helps determine:
•Organ/tissue uptake
•Imaging timing
•Radiation dose to organs

18. Human (Clinical) Studies –Phase I
•Small number of healthy humans.
•Determines:
•Distribution
•Clearance
•Optimal imaging time
•Dose estimation

19. Human Studies –Phase II & III
•Phase II: patients with known disease
•Confirms safety & initial diagnostic/therapeutic effectiveness
•Phase III: large patient group
•Proves overall usefulness (efficacy + safety)

20. Regulatory Path
•Clinical trials performed as Investigational New Drug (IND).
•After data collection →submit New Drug Application (NDA).
•FDA approval is required before commercial use.

21. Quality Control of Radiopharmaceuticals
•Critical for safe human use.
•Parameters checked:
•Radiochemical purity
•Radionuclidicpurity
•Sterility
•Apyrogenicity
•Isotonicity
•pH

22. Radionuclidic Purity –Overview
•Should contain only the desired radionuclide.
•Contaminants increase:
•Give no diagnostic information
•Radiation dose
•Image degradation

23. Example –Iodine Contaminants
•I-123 often contaminated with I-124.
•I-124 emits high-energy gamma rays.
•Increases patient dose & degrades image quality.
•Impurity measured in μCi or kBqper mCiof radionuclide.

24. Limits and Regulations
•Regulatory limits (e.g., Mo-99 in Tc-99m):
•→Max 0.15 μCi Mo-99 per 1 mCiTc-99m
•If no official limit:
•Rule of Thumb ; rad dose to the pt. from the radio-contaminants to <10%

25. Radio nuclidic Purity Over Time
•Purity does not stay constant with time.
•If contaminant half-life > radionuclide →purity degrades over time.
•Purity is highest at production time.
•As radionuclide store it become less pure.

26. Measuring RadionuclidicPurity
•Measured by:
•Gamma spectroscopy
•Using NaI(Tl) or Ge (Li) detectors

27. Radiochemical Purity
●It is the percentage of total radioactivity in the desired chemical form of radionuclide.
●Radionuclide may form several compounds with a given chemical, it is important to ensure
that a given radiopharmaceutical is in desired chemical form

28. Radiochemical Purity
•May not be stable over period of time ....as a result of
○Action of Radiation
○Nature of chemicals

29. Prevention from deterioration
●Stored properly
●Example : radioiodionatedhuman serum albumin RIHSA used as blood pool scanning agent,
may be 99.9% pure (Freshly prepared). With time radioiodine become free ... Interfere with
intended studies
•Amount of contamination depend on storage condition.

30. Detection of impurities
•Common method : thin layer or paper chromatography

31. Chemical purity
•A radiopharmaceutical should contain only desired chemical.
•There are number of chemicals beside the radiochemical of interest.
•But make sure that they are compatible with main chemical in vitro , safe for pt and should not distort
the in vivo function of main chemical.
•Example : Al breakthrough in ⁹⁹Mo –Tc⁹⁹m generator (potential CI)

32. Sterility
•A radiopharmaceutical should be sterile (I.efree from any microbial contamination.) And therefore
should be tested to this effect before use in.patients.
•For short lived radionuclides e.g99mTC and 113m In sterility maintain during their preparation.

33. Apyrogenicity
•Even if preparation is sterile , it may still contain pyrogens that, when I/V administered to a
patient may cause a reaction.
•So test radiopharmaceutical for pyrogenicitybefore use in human.

34. Labelingof Radiopharmaceuticals with Tc-99m
Why Tc-99m?
•Ideal physical and chemical properties
•Easy availability from generator

35. Labelingof Radiopharmaceutical with Tc⁹⁹m
Labelingmethods:
●Direct labeling
●Indirect labeling

36. Labelingof Radiopharmaceuticals with Tc-99m
Key factors affecting labeling:
•pH, reducing agents (like Sn²⁺), and purity of eluate
•Efficiency depends on the chemical formof the drug

37. Tc-99m Pertechnetate
•Orally or iv injected.
•Obtain directly from ⁹⁹Mo-⁹⁹mTcgenerator using saline as a eluding solution.
•In biological system behaves similarly to iodine.
•Use: Thyroid, salivary glands, stomach and choroid plexus.
•Disapperanceof pertechnetate multiexponential function.
•50% dilute into extravascular spaces , 20% to 30% excreted in feces, remaining clear from
plasma with half life of 3 hours.
•Not recomendedfor pt who had imaging with tcpertechnetate upto48h before study.

38. Tc-99m SulfurColloid
•Easily prepared using commercially available kits.
•Colliodsremove by RE cells of body.
•Use: Liver, spleen, bone marrow scans
•Injected IV
•70%-80% dosage localize liver , 3% in spleen, 15%-20% in bone marrow.

39. Technetium-99m-Labeled MAA (Macroaggregated
Albumin)
•Injected iv
•Used in lung imaging.
•90%-95%inj dose localize capillary and precapillary bed of the lungs
•For effective localization MAA size must be between 15 and 75 micrometer.
•Half life 8-12hrs.

40. Technetium-99m-Labeled Polyphosphate,
Pyrophosphate, and Diphosphonate
●Used primarily for bone imaging.
●50–60% localize in skeleton within 15–20 min post-injection
●20–30% excreted by kidneys within 3 hours

41. Technetium-99m-Labeled Polyphosphate,
Pyrophosphate, and Diphosphonate
Comparison:
●Polyphosphate: Slowest plasma clearance (least desirable)
●Diphosphonate: Fastest clearance (most suitable for imaging)
Other Use:
●Useful in myocardial infarction detection

42. Technetium-99m-Labeled Human Serum Albumin
●Blood pool imaging (e.g., heart, placenta)
●Retained in plasma for long duration.
•Not as stable in vivo as albumin labelled with radioiodine or radiochromium.
●therefore , Not suitable for plasma volume determination.

43. Technetium-99m-Labeled Human Serum Albumin
Stability:
●Less stable in vivo compared to radioiodine/radiochromium-labeledalbumin

44. Technetium-99m-Labeled Red Cells (In Vivo Method)
Use:
●Blood pool scanning, especially heart.
Steps Involved:
Step 1: Inject 1/5 of a cold pyrophosphate kit (no radioactivity).
Step 2: After 30 mins, inject Tc-99m pertechnetate.

45. Technetium-99m-Labeled Red Cells (In Vivo Method)
Mechanism:
●Tin (Sn2+) in kit reduces Tc-99m, which binds to red cells.
●90% of Tc-99m binds to red cells.
Advantages:
●Rapid and simple compared to earlier methods.

46. Technetium-99m-Labeled Red Cells (In Vitro Method)
Process:
●Withdraw red cells.
●Incubate with Sn2+ and Tc-99m.
●Re-inject into patient.

47. Technetium-99m-Labeled Red Cells (In Vitro Method)
●Cells may be heat-damaged for spleen imaging.
●Damaged cells: Used to image spleen.
●Colloids (sulfur/tin): Used for liver imaging.

48. Tc-99m Labeled DMSA
(Dimercaptosuccinic Acid)
agent of choice when examining the morphology of the renal cortex.
Renal scans: After IV administration, it rapidly mixes with plasma volume.
Plasma half-life: ~1 hour
Within 2 hours:40%–50% of the dose is taken up by the renal cortex.
~15% excreted in urine.

49. Tc-99m-Labelled DTPA
Uses: Primarily used for kidney imaging.
Administration: Intravenous (IV).
Clearance: Rapidly cleared by kidneys.
Biological Half-life: ~15 minutes in plasma.
Excretion:Over 80% of injected dose excreted in urine.
Urinary recovery between 2 to 3 hours post-injection.

50. Behavior: Intermediate between 99mTc DTPA
and 99mTc DMSA.
Clearance:Slower than DTPAFaster than DMSA
Uptake:Cortex uptake peaks at ~1 hour25% of
dose retained in urine at this time
Use: Primarily for renal imaging.
Other Use: Early-stage detection of myocardial
infarctions (2–3 days post-infarction).
Tecnetium-99m-Labelled Glucoheptonate

51. Purpose: Evaluates renal function; alternative
to iodohippuran.
Clearance: Rapid clearance via active tubular
secretion & glomerular filtration.
Excretion:90% of dose excreted in urine in
normal subjects.
Plasma Binding: Bound to plasma proteins, but
has fast clearance due to reversible binding.
Tecnetium-99m-Labeled Mertiatide (MAG3)

52. Technetium-99m-Labeled HIDA
compounds
Use: Imaging hepatobiliary system.
Clearance:Rapidly cleared by hepatocytes.Blood clearance half-
time: few minutes.
Transit:Fast movement from liver → gallbladder → intestine.70%
of dose reaches intestine within 1 hour.
Excretion:15% via
urine (1st hour).Rest excreted in feces.
Note: Excretion varies with compound (e.g., Diethyl-IDA <
PIPIDA/DISIDA).

53. Tc-99m-Labelled teboroxime (cardiotec)
•Tc-99m-Labeled Teboroxime (Cardiotec)
•Use: Myocardial (heart) imaging.Rapid uptake and clearance from
blood.
•Strength: Fast uptake.Weakness: Quick washout → difficult
imaging.
•Max localization: Liver (33%) @15 mins.
•Excretion: Hepatobiliary system (liver) and kidneys.

54. Technetium-99m-Labeled
Tetrofosmin(Myoview)
•Most recent & approved agent for cardiac imaging.High uptake in:
•Skeletal muscle: 18%
•Heart: 11%
•Liver: 7.5%
•Kidneys: 6.2%
•<5% remains in blood.
•75% excreted in 48 hrs (40% urine, 35% feces).
•Exercise increases excretion.
•Protocol: Exercise scan → 4 hrs → Rest scan.

55. Brain Imaging Agents
. Ceretec,HMPAO,ECD
•Cross blood-brain barrier.
•Ceretec uptake in brain: 7% at 1 min post-injection.
•High regional localization → used in brain perfusion studies.
•Excreted via gastrointestinal tract and kidneys.

56. Radioiodine-Labeled
Radiopharmaceuticals
Use decreased due to Tc-99m.
Still important in thyroid imaging and treatment.
I-131: Treatment of hyperthyroidism, thyroid cancer
I-123: Diagnostic imaging.Preferable for thyroid due to natural
iodine uptake.

57. I-131/I-123 Sodium Iodide
•Administered orally or intravenously.
•Distribution:Absorbed in stomach
•→ spread in extracellular waterTaken up by thyroid, salivary glands,
choroid plexus
•Excretion by 24 hrs:
•75% urine
•15% liver & stool
•4% to 5% GI tract
•2% blood

58. Other Iodine-123 Radiopharmaceuticals
I-123 HippuranFor renal functionRapid kidney clearanceUsed in
renogramsI-123 Isopropylamphetamine (Spectamine)Measures
brain perfusionPromising alternative to FDG-PET

59. Gallium-67 Citrate Use:
•Detects soft tissue tumors & inflammation
•Distribution:30% binds plasma proteins
•Rest → tissues, slow clearance by kidneys
•Excretion by 24 hrs:
•15% urine
•10% blood
•10% feces (1 week)
•Half-life in body: 1–2 weeksRemains active → diagnostic valueMay
cause abdominal image misinterpretation

60. Thallium –201 chloride
•Thallium-201 Chloride
•Used in myocardial perfusion imaging (heart).
•
•Mimics potassium; accumulates in viable myocardial cells.
•
•Indicates ischemic areas (reduced blood flow) due to low uptake.

61. Problems related to
radiopharmaceutical
○calculation of radiation dose
Accurate doses required accurate data about physical decay , characteristics
of radionuclide and its distribution in body .Accurate data of 1
st
is available,
data of latter two is difficult to obtain.
○radiation dose from therapy may be different from that estimated from
diagnostic dosage.
Biological response of different individuals to the same dose varies .

62. Uses of radiopharmaceutical
Despite inability to deliver exact number of gray(or rad) to target , success
has been achieved for treatment of number of diseases.
○I-131 : hyperthyroidism , Cancer of thyroid
○P-32 : Leukemia, polycythemia, bone metastases
○Sr-90: Bone metastases
○P-32,Au-198,Y-90 : A variety of Malignant diseases