Synthesis of 3-[ 18F]fluoromethyl-BTCP and evaluation as a potential PET radioligand for the dopamine transporter in baboons

Abstract

In an attempt to visualize in vivo the dopamine transporter and evaluate its potential as an imaging tool for monitoring dopamine fiber degeneration by positron emission tomography, the 18F-positron-emitting analogue of 3-fluoromethyl-1-[1-(2-benzothienyl)-cyclohexyl]-piperidine, [ 18F]BTCP, was synthetized and tested in a primate model of hemiparkinsonism. [ 18F]BTCP was obtained from cyclotron-produced n.c.a. [ 18F]fluoride (110min half-life) and by nucleophilic substitution from 3-bromomethyl-BTCP with a radiochemical yield of 6% (decay-corrected). After intravenous injection, the cerebral distribution of the radioactivity was observed mainly in cortical areas and cerebral structures enriched in catecholamine reuptake sites such as the caudate-putamen complex and the thalamus. The binding ratio, defined with respect to the cerebellum (taken as a region of non-specific binding), was highest in the thalamus (1.42), intermediate in the putamen (1.36) and lowest in the caudate nucleus (1.17), suggesting that some specific binding occurs in these regions. After saturation of dopamine and norepinephrine transporters by nomifensine, the binding ratio in the thalamus, putamen and caudate nucleus striatum remained essentially unchanged in the non-lesioned hemisphere. When comparing binding ratios between the intact and the dopamine-denervated striatum, there was a modest loss of binding in the denervated striatum, suggesting that degeneration of dopaminergic fibers could be detected using 3-[ 18F]fluoromethyl-BTCP. However due to a high non-specific binding in vivo, the interest of 3-[ 18F]fluoromethyl-BTCP to image the dopamine reuptake system in vivo appears rather limited.