- ELSEVIER SCIENCE INC
3 - (4-Chlorobenzyl)-8-methoxy- 1,2,3,4-tetrahydrochromeno [3,4-c]pyridin-5-one (1), a putative dopamine D-4 receptor antagonist (k(i) = 8.7 nM), was labeled by positron-emitter (C-11) and its pharmacological evaluation was carried out with in vitro quantitative autoradiography and positron emission tomography (PET). C-11-Methylation of a corresponding desmethyl precursor (2) with [C-11]CH3I gave [C-11]1 with greater than or equal to98% 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 [C-11] I shows no specific binding to the D-4 receptors, but a high specific binding to sigma, receptors (IC50 = 105 nM). In the PET study with monkey brain, [C-11] 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 (I mg/kg), a selective sigma(1) receptor agonist, also reduced the radioactivity in the same regions to a similar extent. These results indicate that [C-11] 1 may have some specific binding to the sigma, receptors, which is consistent with the result of in vitro autoradiography. (C) 2002 Elsevier Science Inc. All rights reserved.
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- DOI : 10.1016/S0969-8051(02)00293-7
- ISSN : 0969-8051
- PubMed ID : 12031882
- Web of Science ID : WOS:000175794400011