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

(S)-5-Bromo-N-[(1-cyclopropylmethyl-2-pyrrolidinyl)methyl]-2,3-dimethoxybenzamide (4) has pico-molar in vitro binding affinity to D2 receptor (Ki (D2) = 0.003 nM) with lower affinity to D3 receptor (Ki (D3) = 0.22 nM). In this study, we describe radiosynthesis of [11C]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 [11C]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 [11C]4 exhibited high specific binding in brain regions enriched with dopamine D2/D3 receptors and low level of non-specific binding. In cynomolgus monkeys [11C]4 exhibited high brain uptake reaching 4.4% ID at 7.5 min. The binding in the extrastriatal low density D2-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. [11C]4 is a promising radioligand for imaging D2 receptors in low density regions in brain.

The 11C labelled (S)-5-bromo-N-[(1-cyclopropylmethyl-2-pyrrolidinyl)methyl]-2,3-dimethoxybenzamide ([11C]4) was synthesized and its dopamine D2/D3 receptor binding was evaluated in post-mortem human brain autoradiography and with PET in cynomolgus monkeys.Figure optionsDownload as PowerPoint slide