Brain serotonin receptors are implicated in psychiatric disorders, particularly depression, anxiety and substance abuse Of the 14 subtypes of serotonin receptors identified in brain, the 5HT-1A receptor is a direct target of the atypical anti-anxiety drug buspirone and an indirect target of antidepressant drugs To determine the feasibility of monitoring this receptor in living brain by SPECT imaging, we investigated rhenium analogues of WAY 100635 WAY 100635 is an aryl piperazine that previously has been identified as a PET ligand for brain 5HT1A serotonin receptors In an effort to optimize the affinity and brain uptake of these metal-chelated analogues, several compounds were synthesized with various linkers between the receptor binding moiety and two N2S2 chelate systems In vitro assays of the complexes were conducted in frontal cortex of brain using [3H]8-OH-DPAT a 5HT1A ligand and [3H]7-OH-DPAT to label the D3 dopamine receptor Several compounds displa yed nanomolar affinity for the 5HT1A receptor and one compound was potent at the D3 dopamine receptor Further research on brain uptake and biodistribution is planned in small mammalian species Our successful imaging of the brain dopamine transporter with technetium-labeled probes may extend to other proteins of therapeutic or diagnostic relevance Alan J Fischman, MD, Ph D Department of Nuclear Medicine, Radiology, Massachusetts General Hospital, Boston, MA To develop and evaluate novel PET and SPECT imaging agents as markers for dopamine neurons in Parkinson's disease and other brain disorders To conduct clinical trials with altropane To determine brain occupancy of candidate cocaine medications To determine the effects of chronic administration of candidate medications on brain dopamine systems To evaluate the brain occupancy pf a novel candidate antiparkinsonian drug To develop novel technetium agents Ali Bonab, Ph D , Massachusetts General Hospital Boston, MA Nat Alpert, Ph D , Massachusetts General Hospital Boston, MA To develop methods for quantifying the dopamine transporter using PET imaging of brain Anna-Liisa Brownell, Ph D , Department of Radiology ,Massachusetts General Hospital ,Boston, MA To conduct PET imaging studies with novel and other compounds, for probing the targets of cocaine Peter C Meltzer, Ph D , Organix, Inc Paul Blundell, Ph D To synthesize and evaluate novel tropanes as probes for monoamine transporters, as imaging agents and as therapeutics for cocaine medications and Parkinson's disease To develop novel technetium agents Aloke Dutta, Ph D , Organix, Inc To develop potent and selective GBR analogs for the dopamine transporter Alun G Jones, Ph D , Harvard Medical School Ashfaq Mahmood, Ph D , Harvard Medical School To develop technetium imaging agents for brain dopamine and serotonin systems Alan Davison, Ph D , Massachusetts Institute of Technology To develop technetium imaging agents for brain dopamine and serotonin systems Jack Bergman, Ph D , McLean Hospital, Belmont, MA To measure the effects of chronic cocaine on dopamine systems in brain Allyn C Howlett, Ph D St Louis University, St Louis MO To investigate cannabinoid/dopamine agonists interaction To assess therapeutic potential of cannabinoid antagonists Susan Amara, Mark Sonders, Vollum Institute, Portland OR To determine effects of novel drugs on currents in cells transfected with transporters Susan George, M D , University of Toronto Brian O'Dowd, Ph D ,University of Toronto To measure effects of non-amines on extracellular dopamine levels in vivo Beth Hoffman, Ph D NIH To develop point mutations on the dopamine transporter Philip Seeman, M D , Ph D To develop novel hypotheses on mechanism of action of anti-hyperactivity medications
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