title: Synthesis and evaluation of vesamicol analog (-)-O-[11C]methylvesamicol as a PET ligand for vesicular acetylcholine transporter.
abstract: (-)-O-Methylvesamicol ((-)-OMV) exhibited in vitro a high affinity for vesicular acetylcholine transporter (VAChT) (Ki, 6.7 nM) and a relatively low affinity for sigmal receptor (Ki, 33.7 nM). We prepared (-)-[11C]OMV by a palladium-promoted cross-coupling reaction using [11C]methyl iodide, in a radiochemical yield of 38 +/- 6.9% (n=3), a radiochemical purity of 98 +/- 2.3% (n = 5), and a specific activity of 11 +/- 7.0 TBq/mmol at 30 minutes after EOB (n=5). Then, we evaluated in vivo whether (-)-[11C]OMV has properties as a PET radioligand for mapping VAChT. In rats, the brain uptake of (-)-[11C]OMV was 1.1%ID/g at 5 minutes postinjection, and was retained of a high level for 60 minutes. The brain uptake was significantly inhibited by the co-injection (500 nmol/kg) of cold (-)-OMV (58-66%), (-)-vesamicol (57-65%), and two sigma receptor ligands with modulate affinities for VAChTs: SA4503 (56-71%) and haloperidol (39-64%) in all of the brain regions, including the cerebellum with a low density of VAChTs, but not of sigmal-selective ligand (+)-pentazocine. However, the pretreatment with a large excess amount of (+/-)-pentazocine (50 micromol/kg) reduced the uptake in a different manner in the brain regions: 25% reduction in the striatum with a high density of VAChTs, and a 50-55% reduction in the other regions with a lower density of VAChTs. Ex vivo autoradiography using (-)-[11C]OMV showed a similar regional brain distribution of [3H](-)-vesamicol. In the PET study of the monkey brain, the regional brain distribution pattern of (-)-[11C]OMV was different from that of [11C]SA4503. The uptake of (-)-[11C]OMV was relatively higher in the striatum, was reversible, and an apparent equilibrium state was found at 20-40 minutes. In conclusion, (-)-[11C]OMV exhibited appropriate brain kinetics during the time frame of 11C-labeled tracers and bound mainly to VAChTs; however, the binding to sigmal receptors was not disregarded. Therefore, (-)-[11C]OMV-PET together with help of [11C]SA4503-PET may evaluate VAChTs.
authors.affiliation: Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shiba
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukada
authors.forename: Shingo
authors.initials: S
authors.lastname: Nishiyama
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Mori
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D000882:Haplorhini; D007553:Isotope Labeling / Q000379:methods; D008024:Ligands; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism*
chemical_list: D002250:Carbon Radioisotopes; D008024:Ligands; D010880:Piperidines; D019275:Radiopharmaceuticals; D050494:Vesicular Acetylcholine Transport Proteins; C006189:vesamicol