DOPAMINE TRANSPORTER IMAGING WITH FLUORINE-18 PET

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Positron emission tomography (PET) is sensitive and specific non-invasive imaging technology that can provide information about the functional status of neurotransmitter system in-vivo. Recent effects have focused on the development of PET-based radiotracers for use in studies of the dopamine transporter (DAT) abundance and pharmacology. Changes in the density and function of DAT have been implicated in neurodegenerative and neuropsychiatric diseases such as Parkinson's disease, major depression, Huntington's chorea, schizophrenia, and attention deficit-hyperactivity disorders (ADHD). Out earlier studies have focused on fluorine-18 labeled tropane derivatives, such as FP-CIT, in which the N-methyl group of the tropane was replaced by a [18F] fluoropropyl group. During the Phase I project, we characterized the cerebral monoamine transporter binding affinity of a series of novel fluoralkyl-containing tropane derivatives which showed higher DAT affinity and selectivity than FP-CIT. These new ligands are attractive candidates for development of 18F-labeled PET radiotracers for clinical imaging DAT in human brain. Our objectives on this Phase II project are to further synthesize and pharmacologically evaluate novel- or O-fluoroalkyl tropane derivatives with a view toward one-step simplified 18F-radiolabeling. The most promising compounds' physiochemical properties (lipophilicity) will be evaluated. A facile and rapid method of synthesis of 18F labeled tropane derivatives will be developed for the most promising compound(s). The lead compound in this series (presently BRL-308) will be evaluated by PET imaging and pharmacokinetics, in non-human primates. PROPOSED COMMERCIAL APPLICATIONS: The fluoropropyl analogue of beta-CIT will be a useful radiopharmaceutical if labeled with radionuclides for tomographic imaging. [123I] FP-CIT is currently being marketed for sale to the Nuclear Medicine community. There is a need for [18F] FP-CIT for PET imaging primarily for the research community. The availability of a kit for easy production of [18F] FP-CIT or related improved ligands will meet this need.