title: Positron labeled muscarinic acetylcholine receptor antagonist: 2- and 4-[18F]fluorodexetimide. Syntheses and biodistribution.
abstract: Two 18F-labeled analogues of dexetimides, 2-[18F]fluorodexetimide (2-FDEX) and 4-[18F]fluorodexetimide (4-FDEX), were prepared and evaluated in vivo as possible agents for the study of the muscarinic acetylcholine receptor (mAChR) with PET. Two synthetic approaches, a 2-step reductive alkylation procedure and a 4-step alkylation approach, were investigated. The alkylation approach with higher overall radiochemical yields was used to prepare 2- and 4-FDEX for biodistribution studies. The overall synthesis time for both compounds was 2.5 h and the overall radiochemical yield at end-of-synthesis was 12%. The specific activity was found to be greater than 600 mCi/mumol. Biodistribution studies of 2-FDEX in rats produced striatum-to-cerebellum and cortex-to-cerebellum ratios of 8.6 +/- 1.1 and 8.4 +/- 1.0 at 1 h after injection, and 12.1 +/- 2.1 and 10.7 +/- 2.2 at 3 h, respectively. Substantial radioactivity detected in bone indicated the in vivo defluorination of 2-FDEX. The striatum-to-cerebellum ratio for 4-FDEX was slightly lower at 1 h (5.9 +/- 0.9) but equally high at 3 h (12.3 +/- 2.0) when compared to 2-FDEX, and there was little bone uptake. The uptake of both 2-FDEX and 4-FDEX into mAChR rich brain regions (e.g. striatum, cortex) was blocked by a dose of dexetimide (5 mg/kg). Our results suggest 4-FDEX is a potential PET agent for study mAChR in vivo.
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO 63110.
authors.forename: D R
authors.initials: DR
authors.lastname: Hwang
authors.forename: C S
authors.initials: CS
authors.lastname: Dence
authors.forename: Z A
authors.initials: ZA
authors.lastname: McKinnon
authors.forename: C J
authors.initials: CJ
authors.lastname: Mathias
authors.forename: M J
authors.initials: MJ
authors.lastname: Welch
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D003909:Dexetimide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D018727:Muscarinic Antagonists; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000378:metabolism*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D005462:Fluorine Radioisotopes; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; C067992:2-fluorodexetimide; C067994:4-fluorodexetimide; D003909:Dexetimide; D000109:Acetylcholine