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DEVELOPMENT OF PET AND SPECT LIGANDS FOR MGLUR5 IMAGING

Award Number: R33DA016180
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2002
PERIOD OF PERFORMANCE END DATE: 08/31/2008

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DEVELOPMENT OF PET AND SPECT LIGANDS FOR MGLUR5 IMAGING - DESCRIPTION (provided by applicant): The metabotropic glutamate receptor subtype 5 (mGluR5) is implicated in many psychiatric disorders, including schizophrenia, mood and anxiety disorders, and cocaine addition. Despite the wealth of evidence from preclinical and psychopharmacology studies demonstrating dysfunctional glutamatergic function in these devastating neuropsychiatric disorders, however, to date there is no suitable ligand. We propose to test the feasibility of identifying a radioligand that can be developed into a radiopharmaceutical to image the mGluR5 in vivo with PET or SPECT.The mGluR5 protein structure is characterized by a large extracellular domain and seven transmembrane regions. Most ligands to date are amino acids, which bind at the extracellular domain and generally have only micromolar affinity. The best ligands reported (e.g. MPEP) are non-amino acids and bind in the transmembrane region. Our design strategy is to modify the base structure in such as ways to involve additional amino acids residues in the transmembrane region, thus increasing affinity and selectivity of mGluR5 binding. The first (R21) phase of this proposal we aim to 1) synthesize and evaluate the in vitro pharmacology of new ligands for mGluR5 that can be labeled either with C and F for PET or with I for SPECT; and 2) Radiolabel the ligands with the best pharmacological properties and measure their regional brain uptake in rodents. Compounds that localize in the appropriate brain regions will be further evaluated with pharmacological challenge to assess their vivo specificity. At the end of the this phase, definitive testing of the feasibility of this approach will have been accomplished. If the quantitative criteria defined as milestones for the R21 projects are met, the R33 component will 3) perform PET/SPECT imaging and pharmacokinetic analysis in non-human primates. 4) develop the selected radiotracer into a radiopharmaceutical, perform toxicity and safety tests in preparation for an IND application, and 5) carry out initial imaging trials in healthy human subjects. The studies proposed herein will produce the first radiotracer suitable for imaging the mGluR5 receptor in living humans and will surely serve as the gateway for exploration of the functional state of the glutamatergic system in the living human brain in health and disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2007 ( Subtotal = $268,545 )
2007	2007	INSTITUTE FOR NEURODEGENERATIVE DISORDERS	60 TEMPLE STREET	NEW HAVEN	CT	06510	SOUTH CENTRAL CT	USA	Drug Use and Addiction Research Programs	000	6	9/4/2007	NON-COMPETING CONTINUATION	$268,545
														Subtotal = $268,545

Grand Total All Awards = $268,545

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DEVELOPMENT OF PET AND SPECT LIGANDS FOR MGLUR5 IMAGING

Award Number: R33DA016180

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2002

PERIOD OF PERFORMANCE END DATE: 08/31/2008

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