title: 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 sigma(1) receptors.
abstract: 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 (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]CH(3)I gave [11C]1 with >or=98% of radiochemical purity after HPLC purification and 67-90 GBq/micromol 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 D(4) receptors, but a high specific binding to sigma(1) receptors (IC(50) = 105 nM). 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 sigma(1) 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 sigma(1) receptors, which is consistent with the result of in vitro autoradiography.
authors.affiliation: CREST, Japan Sciences and Technology Corporation, Kawaguchi, Japan. zhang@nirs.go.jp
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.forename: Terushi
authors.initials: T
authors.lastname: Haradahira
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Takashi
authors.initials: T
authors.lastname: Okauchi
authors.forename: Kouichi
authors.initials: K
authors.lastname: Kawabe
authors.forename: Takayo
authors.initials: T
authors.lastname: Kida
authors.forename: Shigeru
authors.initials: S
authors.lastname: Obayashi
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism; D003374:Coumarins / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D005625:Frontal Lobe / Q000000981:diagnostic imaging / Q000378:metabolism; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D010423:Pentazocine / Q000008:administration & dosage; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050638:Receptors, Dopamine D4; D017480:Receptors, sigma / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013788:Thalamus / Q000000981:diagnostic imaging / Q000378:metabolism; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods; D000097605:Sigma-1 Receptor
chemical_list: D003374:Coumarins; D010423:Pentazocine; D011725:Pyridines; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C469348:3-(4-chlorobenzyl)-8-methoxy-1,2,3,4-tetrahydrochromeno(3,4-c)pyridin-5-one; C493601:Drd4 protein, rat