Abstract
891
Objectives: Dopamine reuptake mediated by the dopamine transporter DAT plays a key role in the regulation of dopaminergic signal transduction. Quantitative imaging of the DAT-status in vivo using PET remains of significant clinical relevance. N-4-[18F]fluorobut-2-en-1-ylated tropane derivatives like LBT-999 1a (R”=Me) or FBCFT (R”=F) show both, good affinity and high selectivity to the DAT. We deduced a SAR-study to determine the contribution of 4-fluorinated, conformationally restricted C4 chains R’ at the tropane nitrogen to affinity, pharmacokinetic properties and selectivity.
Methods: 16 novel 3β-phenylnortropanes were prepared from cocaine hydrochloride (chosen examples in table). All compounds were evaluated in hEK cell lines stable transfected with hDAT, hSERT and hNET for monoamine reuptake inhibition.
Results: 1d-e show low nanomolar affinity and high selectivity. Compared to LBT999 and CFT (WIN35,428), other established selective DAT-ligands, the novel candidates 1d-f provide improved affinity and selectivity.
Conclusions: A set of novel tropane derivatives containing a conformational restricted C4-chain has been prepared for in vitro and in vivo SAR studies. Preliminary evaluations in rodent are presently ongoing with [18F]1c-e for comparative studies of dopaminergic signal pathways involving [18F]FP.
- Society of Nuclear Medicine, Inc.