DOPAMINE TRANSPORTER IMAGING WITH FLUORINE-18 PET

DESCRIPTION (provided by applicant):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.
PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE