METALS IN MEDICINE APPLICATIONS OF METALS IN MEDICINE

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

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

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

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

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

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

METALS IN MEDICINE

METALS IN MEDICINE

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

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

METALS IN MEDICINE “METAL” ISOTOPE REQUIREMENTS ( Emission (g, b+, b-, a) ( Radionuclide purity ( Specific activity ( Half-life ( Chemical/physical properties ( Ease of production/cost

METALS IN MEDICINE

METALS IN MEDICINE

METALS IN MEDICINE Tc-99 m HMPAO (Ceretec)

METALS IN MEDICINE 99 m. Tc HMPAO (Ceretec)

Ictal HMPAO SPECT Inter - Ictal HMPAO SPECT PET

METALS IN MEDICINE 99 m. Tc-MIBI

METALS IN MEDICINE

METALS IN MEDICINE 99 m. Tc-Trodat-Brain Receptor Imaging

METALS IN MEDICINE 99 m. Tc-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

METALS IN MEDICINE Known Receptor Ligand Isotope Conjugate Design Integrated Design

METALS IN MEDICINE

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

METALS IN MEDICINE Radiopharmaceuticals R&D Interests

METALS IN MEDICINE 99 m. Tc-RGD Peptide

METALS IN MEDICINE Radiopharmaceuticals R&D Interests ( Apoptosis ( Angiogenesis (avb 3 antagonists, MMP’s) ( Growth factors (VEGF, EGF) ( Receptor-based Tumour targeting (Breast, Melanoma and Prostate) ( Peptides ( Cell labelling-proteomics

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

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, Mo. Abs) and new isotopes Synergistic effects (Molecular Inhibitors, Hypoxia, Angiogenesis, Selective Cytotoxicity

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