title: Radiosynthesis and ex vivo evaluation of [11C]-SIB-1553A as a PET radiotracer for beta4 selective subtype nicotinic acetylcholine receptor.
abstract: [11C]-SIB-1553A ((+/-)-4-[2-((N-[11C]-methyl)-2-pyrrolidinyl)ethyl]thiophenol) was labelled with carbon-11 (t1/2=20.4 min) and evaluated in vivo as potential radiotracer for noninvasive assessment of the beta4 subunit nicotinic acetylcholine neurotransmission system with positron emission tomography (PET). The labelling precursor was obtained within five steps from N-Boc-prolinal in 45-56% overall yields. The radiosynthesis of [11C]-SIB-1553A was achieved by a selective N-[11C]-methylation in 32 min with a radiochemical purity greater than 97%, 7.5-30 GBq/micromol of specific radioactivity and 55-65% radiochemical yield (decay corrected, based on [11C]methyl iodide). The ex vivo pharmacological profile of [11C]-SIB-1553A was evaluated in rats with biodistribution studies in organs and in brain structures by autoradiography. The radiotracer uptake in the brain reached 0.49 %ID/g at 10 min and no brain radiometabolite was detected 40 min after intravenous injection. The quantification of radioactivity in various cerebral structures indicated a significantly higher radioactivity level at 15 min than at 30 min. Among the beta4 nAChR subunit-rich structures studied in the rat brain, only the thalamus at 15 and 30 min and the hippocampus at 30 min showed significantly higher uptake. Moreover, competition studies performed with SIB-1553A (15 min before the radiotracer injection) revealed only a low specific binding estimated to 7% of the total binding at 15 min and 13% at 30 min.
authors: CEA, DSV, I2BM, CINAPS, LDMTEP, Caen, F-14074, France. sobrio@cyceron.fr
authors: Franck
authors: F
authors: Sobrio
authors: Thomas
authors: T
authors: Quentin
authors: Martine
authors: M
authors: Dhilly
authors: Thomas
authors: T
authors: Bourdier
authors: Sylvie
authors: S
authors: Tymciu
authors: Danièle
authors: D
authors: Debruyne
authors: Louisa
authors: L
authors: Barré
mesh_terms: D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D010636:Phenols / Q000737:chemistry* / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry; D021122:Protein Subunits; D011759:Pyrrolidines / Q000737:chemistry* / Q000493:pharmacokinetics*; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000032:analysis* / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: C119207:4-((2-(1-methyl-2-pyrrolidinyl)ethyl)thio)phenol hydrochloride; D002250:Carbon Radioisotopes; D010636:Phenols; D021122:Protein Subunits; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic; D011392:Proline; C046026:prolinal