Positron emission tomography (PET) is sensitive and specific non-invasive imaging technology that can provide information about the functional status of neurotransmitter systems in-vivo. Recent efforts 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). Our earlier studies have focused on fluorine-18 labeled tropane derivatives, such as FP-C1T, in which the N-methyl group of the tropane was replaced by a [S18FJ 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-C1T. These new ligands are attractive candidates for development of ?8F-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 N- or 0-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.
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