[(11)C]cyclopropyl-FLB 457: A PET radioligand for low densities of dopamine D(2) receptors

: Airaksinen AJ, Nag S, Finnema SJ, Mukherjee J, Chattopadhyay S, Gulyas B, Farde L, Halldin C

Publisher: PERGAMON-ELSEVIER SCIENCE LTD

: 2008

: Bioorganic and Medicinal Chemistry

: BIOORGANIC & MEDICINAL CHEMISTRY

: BIOORGAN MED CHEM

: 16

: 13

: 6467

: 6473

: 7

: 0968-0896

DOI: https://doi.org/10.1016/j.bmc.2008.05.039

(S)-5-Bromo- N-[(1-cyclopropylmethyl-2-pyrrolidinyl)methyl]-2,3-dimethoxybenzamide (4) has pico-molarin vitro binding affinity to D(2) receptor (K(i) (D(2)) = 0.003 nM) with lower affinity to D(3) receptor (K(i) (D(3)) = 0.22 nM). In this study, we describe radiosynthesis of [(11)C]4 and evaluation of its binding characteristics in post-mortem human brain autoradiography and with PET in cynomolgus monkeys. The 11C labelled 4 was synthesized by using [(11)C] methyltriflate in a methylation reaction with its phenolic precursor with good incorporation yield (64 +/- 11%, DCY) and high specific radioactivity > 370 GBq/mu mol (> 10 000 Ci/mmol). In post-mortem human brain autoradiography [(11)C]4 exhibited high specific binding in brain regions enriched with dopamine D(2)/D(3) receptors and low level of non-specific binding. In cynomolgus monkeys [(11)C]4 exhibited high brain uptake reaching 4.4% ID at 7.5 min. The binding in the extrastriatal low density D(2)-receptor regions; thalamus and frontal, parietal, temporal, and occipital cortex, was clearly visible. Pre-treatment with raclopride (1 mg/kg as tartrate) caused high reduction of binding in extrastriatal regions, including cerebellum. [(11)C]4 is a promising radioligand for imaging D2 receptors in low density regions in brain. (c) 2008 Elsevier Ltd. All rights reserved.