1. Copyright
All images in this presentation are the property of Jane Hanrahan unless otherwise referenced.

2. Dr Jane Hanrahan janeh@pharm.usyd.edu.au
Radiopharmaceutics
Dr Jane Hanrahan

3. Ideal Radiopharmaceuticals
Maximum Diagnostic Information with Minimum Risk
Half-life should be short - isotope has high specific activity
ie rapid decay rate, high No. of dps per weight of material
No particulate radiation emission - want pure g
ie no -, +
g energy high enough to be detected emanating from deep tissue - but low enough to be detected efficiently
Ideal energies 120 to 240 keV

4. Ideal Radiopharmaceuticals
Radionuclide should be an element with variable chemistry
Enables preparation of a wide range of compounds for different diagnostic purposes
Radioisotope should be carrier-free
Want to maximise activity/g - no cold material, reduces toxicity problems
Large scale production is achievable and economical

5. Technetium-99m (99mTc) T1/2 = 6.02 h Decays by isomeric transition
High specific activity
Decays by isomeric transition
99Mo mTc (excited state) Tc (ground state)
Pure -emission with energy 140 keV
Known valences 2, 3, 4, 5, 6, 7 Variable chemistry, most common Tc3+, Tc4+
Readily prepared carrier free

6. Technetium-99m (99mTc) 99Mo (67 h) 99mTc (6 h) 99Tc (2.1 x 105 y) 99Ru
86.3 %
metastable
99Mo
(67 h)
99mTc
(6 h)
13.7 %
Isomeric transition Pure  emission
99Tc
(2.1 x 105 y)
99Ru
(stable)

7. Radionuclide Generators
Ideal Radionuclide Generator
Sterile and pyrogen free
Saline eluent
Mild chemical conditions
Room temperature storage
Ideal gamma-emitting daughter nuclide
No parent present in eluent
Parent half-life short enough so that production of daughter is rapid enough, but not too rapid.

8. Radionuclide Generators
Ideal Radionuclide Generator
Daughter nuclide has varied chemistry to allow production of many different radiopharmaceuticals
Grand-daughter nuclide is very long-lived or stable
Shielding of generator is not too difficult
Separation is simple and does not require a great deal of human intervention
Generator is easily recharged by a readily available parent radionuclide

9. Radionuclide Generators

10. 99Mo/99mTc Generator most widely used generator system
mother nuclide 99Mo (t1/2=67 h) decays into the daughter nuclide 99mTc (t1/2=6 h)
Milking cow analogy
Basics of Radiopharmacy, B.A Rhodes & B.Y.Croft, Chapter 9, Generator Systems. (1978)

11. Other Generator Systems

12. Quality Control Impurities eluted with the Na99mTcO4 in the saline.
Alumina Breakthrough
Radiochemical purity pH
Sterility
Apyrogenicity

13. Quantification Radioactivity Activity
Number of disintergrations per second (Bq)
Rate of disappearance of radionuclide
- dN dt  N
- dN dt = kN
where t
1/2 =
ln2 k
1/2 t =
ln2 k
k=1
N = number of radioactive nuclei
k= constant specific for each isotope

14. Quantification
Exponential decay
At = A0e-kt
Radioactivity
(Bq)
time

15. Example 1 How many moles of 99Mo does 15 GBq represent, t1/2=67h N =
- dN dt = kN
15 GBq = 15 x 10 9 Bq
1/2 t =
ln2 k
15 x 10 9
dps
= 0.693/(67x60x60)
N =
sec-1
2.89 x 10-6
= 2.89 x 10-6 sec-1
= 5.33 x 1015 atoms
Avogadro’s No. = x 1023
No. of moles = No. of atoms
Avogadro’s No.
= 5.33 x 1015
= 8.85 x 10-9 moles
6.023 x 1023

16. Example 2 How many grams of 99Mo does 15 GBq represent, t1/2=67h
From previous slide
15 GBq = 8.85 x 10-9 moles
1 mole 99Mo = 99 gram
Therefore 8.85 x 10-9 moles = 8.85 x 10-9 moles x 99 grams
= 8.76 x grams
= µg

17. Example 3 At = A0e-kt = 15e-(ln2/67)72 = 15 x 0.475 = 7.125 GBq
86.3 % of 99Mo decays to 99mTc with a half life of 67 hours. A 99mTc generator is filled with 15 GBq of 99Mo at 9 am on Friday morning and the 99mTc is eluted from the generator with 90 % efficiency, how much activity of 99mTc per ml can we get from the generator at 9 am on the following Monday morning in a 10ml elution.
At = A0e-kt = 15e-(ln2/67)72
= 15 x = GBq
99mTc activity in generator = x = GBq
Amount eluted = 0.9 x = 5.53 GBq
= GBq/ml = 553 MBq/ml

18. Example 4 At 9am, solution has 533 MBq/ml
At 2 pm on the same Monday as the original elution, what volume of the previously eluted solution would need to be dispensed for a skeletal scan requiring 250 MBq of 99mTc.
t1/2 99mTc = 6 h
At 9am, solution has 533 MBq/ml
Therefore at 1 pm, activity of solution is
At = A0e-kt = 553e-(ln2/6)5
= 533 x = MBq/ml
For 250 MBq, volume of solution = 250/308
= 0.81 ml

19. Mechanism of Localisation
Simple Diffusion
- net movement of particles (molecules) is from an area of high concentration to low concentration.
- normal versus abnormal distribution using Na99mTcO4
eg breakdown of blood brain barrier due to tumours or infarct damage in brain

20. Mechanism of Localisation
Active transport
Uptake radionuclide from blood using normal biochemical processes
e.g. thyroid trapping of 123I or Na99mTcO4 or hepato-billiary imaging
Renal imaging - 99mTc complexed with DTPA (diethylene triamine pentaacetic acid)
Outflow obstruction
Renal artery narrowing
Vesico-uretic reflux
Renal transplant assessment
2 TcO Sn H Tc Sn H2O
DTPA

21. Renal Imaging with 99mTc-DTPA

22. Mechanism of Localisation
Cell Sequestration
Liver, spleen and bone marrow uptake of colloidal particles by reticulo-endothelial (Kupfer) cells
eg technetium sulfide colloid 99mTc2S4 Renal imaging
Particle size ~ 0.1 µm trapped in liver or spleen
Re2S7 is used as a carrier
2HCl Na2S2O H2SO NaCl + H2S + SO2
2 H H2S TcO Tc2S H2O

23. Mechanism of Localisation
Capilliary Blockade
Large particles trapped by lung arterioles (~ 20 µm)
eg for pulmonary perfusion studies
99mTc labeled macroaggregated albumin (MAA)
or 99mTc labeled macroaggregated ferric hydroxide
Ventilation studies - radioactive gas 133Xe
or aerosol radiopharmaceuticals
99mTc as carbide - “Technegas”
99mTc as sulfur colloid
Inhallation then washout - airway obstruction “hotspot”
TcO Tc Tc(OH)4
reduction
-OH + FeSO4

24. Capilliary Blockade

25. Mechanism of Localisation
Compartmental localisation
- placement of a radiopharmaceutical in a fluid space and maintaining it there long enough to image that fluid space. e.g. Retention of labeled 99mTc-labelled RBC or proteins in vascular pools
Methods
Remove blood sample & incubate with Na99mTcO4 for 15 min and then administer
“Pre-tinning” - administer SnCl2 in saline, wait 30 min, then administer labelled RBC ( ~ 700 MBq Na99mTcO4)
“Gated” heart studies - collect images in synchrony with ECG at rest and under stress

26. Labeling RBCs

27. Mechanism of Localisation
Chemisorption
interaction of labelled phosphate complexes with bone
Skeletal imaging - metabolically active sites
- soft tissue tumours
- metastatic lesions
- rheumatoid arthritis
Methylene diphosphate
Na99mTcO4 + SnCl Tc phosphate compound

28. Mechanism of Localisation
Specific cell binding
preferential uptake by tumour cells
eg labelled tumour associated marker compounds or monoclonal antibodies

29. Radiopharmaceuticals for Tumour Imaging
131I (sodium iodide)
- thyroid
67Ga (gallium citrate)
- lymphoma, hodgkin’s disease, lung tumours, bone tumors
- Decays by electron capture (EC) t1/2 78 h
- g energies, 93 keV (40 %), 184 keV (24 %), 296 keV (22 %)
- 67Ga binds to transferin in plasma
- Biodistribution is non-specific
- Uptake is influenced by a number of factors

30. Radiopharmaceuticals for Tumour Imaging
111In (complexed with Bleomycin or monoclonal antibodies)
- t1/2 78 h
-  energies, 173 keV and 247 keV
protein
chelating groups

31. Mechanism of Localisation
8. Specific Receptor Binding
Mainly in CNS
[11C]-Raclopride (dopamine receptor antagonist
[11C]-Flumazenil at GABA-benzodiazepine site