The objective of this proposal is to develop radioligands suitable for Positron Emission Tomography (PET) that bind potently and selectively to metabotropic glutamate (mGlu) receptors. The development of a PET radioligand for imaging mGlu receptors would be useful not only for exploring the functions of these receptors but also for the treatment of schizophrenia. The R21 phase of the proposal includes radiolabeling four bicyclic amino acids with carbon-11 labeled cyanide. Three of the ligands will be labeled under Bucherer- Bergs conditions and the fourth by nucleophilic displacement. Initial evaluation of the radiolabeled compounds will be done in mice. Ligands that show sufficient uptake and proper biodistribution in mice will be evaluated further by PET imaging in baboons. The R33 phase will begin with dosimetry studies in mice. Rats will be used for initial drug occupancy studies with a small animal PET scanner. Further pharmacology, dosimetry and modeling studies will be conducted through PET imaging of baboons. Drug occupancy and ketamine induced glutamate release studies will also be performed in baboons. Toxicology testing will be performed by Eli Lilly & Co. at no cost on one or two of the lead compounds so that up to 2 physician sponsored IND applications can be submitted to the FDA for future clinical studies in humans. Once an approved IND is obtained, initial human studies will begin either at the end of Year 3 or the beginning of Year 4. The chosen radiotracers will then be used in human applications in Year 5. The choice of which ligand will be used in humans will be based upon the behavior of these 2 ligands in rodent and baboon studies which will be examined with respect to feasibility for occupancy studies or intrasynaptic measurement of ketamine induced glutamate release. Proof of principle studies will then be carried out in humans with one or both candidate radioligands. These studies will demonstrate the feasibility of measuring occupancy vs. dose of inhibitor. This will test the hypothesis that a significant separation of occupancy will be observed in the anxiolytic vs. antipsychotic dose extrapolated from rodent and baboon. The other human experiment will be to try to measure glutamate release following ketamine challenge based on the preliminary animal work in baboons. Both human experiments will show the feasibility of two important human applications for mGluR2/3 PET ligands.
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