B12 - Development of New Rradiotracers for the In-Vivo Assessment of Biological Functions and Drug Interactions

The main objective of this Action was to promote co-operation in the development of radiotracers for in-vivo biomedical investigations (making use of diverse European resources for this purpose). The labelling of these precursors with these radionuclides; the evaluation of the biological effectiveness in experimental animal models; performing clinical trials and evaluation of the benefit of the new radiopharmaceuticals; providing pharmaceutical standards of preparation for safe application of the radiotracers (quality assurance programme); collaboration between university and pharmaceutical industry with respect to the utilisation of nuclear medicine probes in drug development.

The scientific programme focused on five important and challenging areas:

1. Radioligands for brain receptors
Neuropsychiatric disorders such as depression, dementia, Alzheimer’s disease, schizophrenia, drug abuse – are all of great socio-economic impact but still very poorly understood with respect to brain chemistry and physiology. PET and SPECT are unique techniques for the investigation of these aspects of disease in vivo, provided that suitable radiotracers can be developed.

2. Radioligands for heart receptors
Cardiac disease is of obvious socio-economic impact. There is substantial evidence for sympathetic drive in the aetiology of cardiac dysfunction. However, direct observation of the changes occurring in the sympathetic nervous system during disease progression is hampered by a lack of radioligands for measurements on pre- and postsynaptic adrenoceptors in living human subjects with PET or SPECT. The focus of the Action is on developing radioligands for post-synaptic adrenoceptors. These might be expected to yield valuable clinical information and complementary to the information obtainable with presynaptic radioligands.

3. Radiolabelled biological active peptides
Many properties of peptides make them attractive vectors for targeting cancer, a strategy already explored successfully for somatostatin. However since many frequently occurring and devastating tumours (small cell lung carcinoma, colon carcinoma or mengioma) do not express somatostatin receptors, it is imperative to search for alternative neuropeptide receptors expressed by these tumours. Recent evidence reports that such malignant lesions, like small cell lung cancer, colon carcinoma and certain mengiomas, express high affinity and density bombesin and neurotensin receptors on the tumour cell membrane. For this purpose, peptide-based analogues with prolonged plasma life and preserved biological action are properly modified to incorporate the radionuclide of choice. Tagging with 18F, 11C and 123I (or 99mTc) useful for PET and SPET respectively are pursued.

4. Radiolabelled Enzyme [Inhibitors and substrates] function tracers
Enzyme inhibition frequently constitutes the molecular basis for the effectiveness of powerful therapeutic agents. Progressively, new more powerful and more specific enzyme inhibitors are designed and with them new therapeutic agents and consequently new radiotracers also for diagnostic purposes could be developed. The Action is focusing on adrenal-hydroxylase and its visualisation using endocrine radiopharmaceutical such as 11C-metyrapone and 11C-etomidate.

5. Technetium chelates
About 85% of nuclear medical diagnoses are performed with Tc labelled pharmaceuticals. Whereas the research was mainly concerned with biological properties which allow relatively unspecific functional imaging as in brain or myocardium perfusion studies, nuclear medicine is now requiring more and more physiological information on low capacity, high specific molecular targets. To meet the requirements of new technetiurn-based compounds called the “third generation” of Tc radiopharmaceuticals, there is a demand for Tc tracers able to undergo molecular interactions with the target tissue.

The work involved synthesis of new chelating systems having optimal properties, complexation with technetium and rhenium as well as studies of relationships between physico-chemical parameters and biodistribution in animals.