PET RADIOTRACER DEVELOPMENT FOR DOPAMINE D4 RECEPTORS

Columbia Univ New York Morningside, New York NY

Investigators

Abstract

DESCRIPTION: (Applicant's abstract) There is no selective radiotracer for use in positron emission tomography (PET) to label dopamine D4 receptor sites in vivo in human brain. The dopamine D4 receptor may be particularly important for schizophrenia research since a 4 to 6-fold increase in the number of the D4 receptor in the striatum of schizophrenic patients has been reported. Lacking selective D4 radiotracers, the number of D4 receptor sites has been estimated using a subtraction of binding using non-selective ligands labeling D2+D3+D4 receptors and those labeling D2+D3 sites. We have synthesized 5 new phenylpiperazine compounds based on the chemical structure of L-745879, a D4 ligand, with the intent of labeling the compounds with positron emitting nuclides such as fluorine-18 or carbon-11. Using in vitro binding assays, we have found that the flurophenyl-piperizine and methoxyphenyl-piperazine derivatives possess high affinity (0.7-4 nM) for D4 receptors and high selectivity (500-800-fold) over D2 receptors. Based on these preliminary results, we propose to 1) characterize the new compounds in vitro to examine possible interactions with serotonin-1A,2A, dopamine D1 or D3 receptors; 2) label the compounds with 18F or 11C; and 3) characterize the binding properties of the radiotracers in vivo in rodents.