[11C]Cyclopropyl-FLB 457: a PET radioligand for low densities of dopamine D2 receptors

Abstract ( S )-5-Bromo- N -[(1-cyclopropylmethyl-2-pyrrolidinyl)methyl]-2,3-dimethoxybenzamide ( 4 ) has pico-molar in 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 11 C 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/μmol (>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 D 2 receptors in low density regions in brain.