The goal of this collaboration between academia and industry is to produce a safe, publicly owned radiopharmaceutical for imaging group Il metabotropic glutamate receptors (mGluRs) with positron emission tomography (PET). New glutamatergic drugs are fast being developed to treat neurodegenerative disorders, anxiety disorders, and psychoses, some of which are major American health problems. However, no effective radioligands for imaging this family of receptors in vivo have been reported. Central to this application is an ongoing strong collaborative effort between researchers at Eli Lilly, Inc. and Columbia University, including a focused project plan that fully utilizes the unique strengths of both institutes as is geared towards radiotracer development. To solidify the successful development of effective mGluR tracers for in vivo PET imaging, this project centers on antagonist-based radiotracers, including molecules that possess higher affinity and much less hydrophilicity than known mGluR agonists such as LY354740 and LY379268. Target candidate radioligands with potentially higher affinity than the group IT mGluR antagonist LY341495, but containing groups readily amenable to labeling with PET radionuclides, will therefore be synthesized and highly evaluated. Researchers at Columbia University will carry out organic and radiochemical syntheses and perform in vivo characterization of new tracers, including rodent, non-human primate and human PET studies. Eli Lilly will provide structure/activity data and expert chemistry advice, characterization of ligands against cloned human mGluRs, and toxicity testing performed to industry and FDA standards. The R33 phase includes the filing of an IND application, and characterization of the tracer via human PET imaging, including whole body dosimetry, test-retest analysis and blocking studies. Successful completion of this project will provide an effective method to non-invasively probe the status and function of mGluRs in humans by PET imaging techniques. Radiolabeled mGluR antagonists will additionally facilitate in vivo dose-receptor occupancy determinations of new drugs targeted to these sites via PET methods. The tools and methods developed will be made readily available to interested researchers, and federal grant applications will subsequently be submitted to explore the role of mGluRs in certain neuropsychiatric and neurodegenerative disorders by PET imaging.
