Synthesis and evaluation of 3-(4-chlorobenzyl)-8-[11C]methoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one:a PET tracer for imaging sigma1 receptors

3-(4-Chlorobenzyl)-8-methoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one (1), a putative dopamine D4 receptor antagonist (ki = 8.7 nM), was labeled by positron-emitter (11c) and its pharmacological evaluation was carried out with in vitro quantitative autoradiography and positron emission tomography (PET). 11C-Methylation of a corresponding desmethyl precursor (2) with [11C]CH3I gave [11C]1 with >98% of radiochemical purity after HPLC purification and 67_90 GBq/mumol of specific activity at the end of synthesis. The in vitro autoradiography using rat brain sections demonstrated that [11C]1 shows no specific binding to the D4 receptors, but a high specific binding to sigma1 receptors(IC50=105nM). In the PET study with monkey brain, [11C]1 was highly taken up by the brain and trapped in the brain for at least 90 min. The distribution pattern of radioactivity in the brain was striatum > thalamus > frontal cortex > cerebellum, which was same as the result of in vitro autoradiography. Pre-treatment with non-radioactive 1 (1 mg/kg) produced a significant reduction of radioactivity in all the regions including the cerebellum. Pre-treatment with (+)pentazocine (1 mg/kg),a selective sigma1 receptor agonist, also reduced the radioactivity in the same regions to a similar extent. These results indicate that [11C]1 may have some specific binding to the sigma1 receptors, which is consistent with the result of in vitro autoradiography