1. RADIOPHARMACEUTICAL R & D
METALS IN MEDICINE
APPLICATIONS OF
METALS IN MEDICINE
AT ANSTO
RADIOPHARMACEUTICAL R & D
Andrew Katsifis
19 January 2004

2. THE RADIOTRACER the idea the tool the concept Henri BECQUEREL George
HEVESY
Claude BERNARD

3. Human Molecular Imaging in Nuclear Medicine RADIOLABELLING
RADIOPHARMACOLOGY
PET SPECT
Precursor
Radionuclide
Injection
Purification
QC/QA
Human
Radiopharmaceutical

4. Radiopharmaceuticals R&D
METALS IN MEDICINE
Radiopharmaceuticals R&D
Multidisciplinary group: Chemists, Biologists, Pharmacologists, Physicists.
Synthetic Chemistry- Ligand, Conjugates
Drug Synthesis-Receptor Molecules
Separation and Analytical technologies
In vitro and In vivo evaluation (Animal Models)
Autoradiography, Metabolite Analysis
Radionuclide Source- Cyclotron and Reactor
SPECT-CT Animal Imaging(CT-SPECT, PET)
Clinical Trials
Extensive national and international links

5. METALS IN MEDICINE Gamma Camera
Compact system designed for animal studies
Dual-head gamma cameras with CT
Pinhole Collimators

6. METALS IN MEDICINE OBJECTIVES
Radiopharmaceuticals R&D are Developing Target-Specific Radiolabeled Pharmaceuticals for Diagnosis and Therapy of Disease
PURPOSE

7. METALS IN MEDICINE

8. METALS IN MEDICINE

9. RATIONALE FOR RADIOPHARMACEUTICAL DESIGN
METALS IN MEDICINE
RATIONALE FOR RADIOPHARMACEUTICAL DESIGN
Few Metals Target Specific Tissues/Organs
201Tl mimics K, 67Ga-Fe and 89Sr-Ca
For biological activity most other “metallic” radioisotopes must be chelated to form complexes or linked to specific targeting entities

10. RATIONALE FOR RADIOPHARMACEUTICAL DESIGN
SMC Briefing
METALS IN MEDICINE
RATIONALE FOR RADIOPHARMACEUTICAL DESIGN
Selection of radioisotope for biological use is primarily determined by the isotope’s decay characteristics
Radiopharmaceutical design is based on the intended use, targeting molecules and the physico-chemical properties of isotope.
Nature of the complex will determine biological activity
Slide 4: Who is it for?
ANSTO Medical Systems

11. “METAL” ISOTOPE REQUIREMENTS
SMC Briefing
METALS IN MEDICINE
“METAL” ISOTOPE REQUIREMENTS
Emission (g, b+, b-, a)
Radionuclide purity
Specific activity
Half-life
Chemical/physical properties
Ease of production/cost
Slide 4: Who is it for?
ANSTO Medical Systems

12. METALS IN MEDICINE

13. METALS IN MEDICINE

15. METALS IN MEDICINE
Tc-99m HMPAO
(Ceretec)

16. METALS IN MEDICINE
99mTc HMPAO
(Ceretec)

17. Inter - Ictal HMPAO SPECT
PET

18. METALS IN MEDICINE
99mTc-MIBI

19. METALS IN MEDICINE

20. 99mTc-Trodat-Brain Receptor Imaging
METALS IN MEDICINE
99mTc-Trodat-Brain Receptor Imaging

21. METALS IN MEDICINE
99mTc-TRODAT-1 SPECT intransverse views of healthy volunteer (A)and of patients with stage I (B) and stage II (C) Parkinson’s disease. Asymmetric striatal uptake was observed, with more profound loss contralateral to symptoms or more affected limbs.

22. METALS IN MEDICINE Known Receptor Ligand Receptor Ligand
Isotope
Isotope
Conjugate Design
Integrated Design

23. METALS IN MEDICINE

24. METALS IN MEDICINE Receptor target identical
Receptor affinity identical
Pharmacokinetics different
Unit target uptake different
Biodistribution different
Clearance rate different
Clearance route different
Metabolism different
Stability is different

25. Radiopharmaceuticals R&D Interests
METALS IN MEDICINE
Radiopharmaceuticals R&D Interests

26. METALS IN MEDICINE
99mTc-RGD Peptide

27. Radiopharmaceuticals R&D Interests
METALS IN MEDICINE
Radiopharmaceuticals R&D Interests
Apoptosis
Angiogenesis (avb3 antagonists, MMP’s)
Growth factors (VEGF, EGF)
Receptor-based Tumour targeting (Breast, Melanoma and Prostate)
Peptides
Cell labelling-proteomics

28. METALS IN MEDICINE Radiotherapy External beam
Brachytherapy (Radioactive implants)
Restenosis
Particulates (Sirtex-spheres)
Systemic -Radionuclide Therapy (Zevalin-Lymphoma)

29. Systemic -Radionuclide Therapy
METALS IN MEDICINE
Systemic -Radionuclide Therapy
Non-invasive delivery of selective radiation to tumours
Combination of brachytherapy and chemotherapy
Limited toxicity- long term effects compare favourably with those of chemotherapy and external beam therapy.
Promising- Advances in molecular targeting technologies (receptors, peptides, MoAbs) and new isotopes
Synergistic effects (Molecular Inhibitors, Hypoxia, Angiogenesis, Selective Cytotoxicity

30. METALS IN MEDICINE Opportunities
Improvements in targeting strategies-Selectivity and Spepcificity
Reduced Toxicity- clearance
Drug-Delivery
Radionuclide Availability and Costs
Regulatory
Medical Infrastructure