title: Neuroimaging of the vesicular acetylcholine transporter by a novel 4-[18F]fluoro-benzoyl derivative of 7-hydroxy-6-(4-phenyl-piperidin-1-yl)-octahydro-benzo[1,4]oxazines.
abstract: Phenylpiperidinyl-octahydro-benzo[1,4]oxazines represent a new class of conformationally restrained vesamicol analogues. Derived from this morpholine-fused vesamicol structure, a new fluorine-18-labeled 4-fluorobenzoyl derivative ([(18)F]FBMV) was synthesized with an average specific activity of 75 GBq/micromol and a radiochemical purity of 99%. The radiolabeling method included an exchange reaction of a 4-nitro group of the precursor by fluorine-18, a reduction procedure to eliminate excess of the nitro compound, followed by a high-performance liquid chromatography purification. [(18)F]FBMV demonstrates (i) a moderate lipophilic character with a logD(pH7.0) 1.8+/-0.10; (ii) a considerable binding affinity to the vesicular acetylcholine transporter (VAChT) (K(i)=27.5 nM), as determined using PC12 cells transfected with a VAChT cDNA, and a low affinity to sigma(1,2) receptors (K(i) >3000 nM); (iii) a good uptake into the rat and pig brains; (iv) a typical accumulation in the VAChT-containing brain regions; and (v) an approximately 20% reduction in cortical tracer binding after a specific cholinergic lesion using 192IgG-saporin. [(18)F]FBMV exhibits another PET marker within the group of vesamicol derivatives that demonstrates potentials in imaging brain cholinergic deficits, while its usefulness in clinical practice must await further investigation.
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Leipzig 04103, Germany. sord@medizin.uni-leipzig.de
authors.forename: Dietlind
authors.initials: D
authors.lastname: Sorger
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheunemann
authors.forename: Johnny
authors.initials: J
authors.lastname: Vercouillie
authors.forename: Udo
authors.initials: U
authors.lastname: Grossmann
authors.forename: Steffen
authors.initials: S
authors.lastname: Fischer
authors.forename: Achim
authors.initials: A
authors.lastname: Hiller
authors.forename: Barbara
authors.initials: B
authors.lastname: Wenzel
authors.forename: Ali
authors.initials: A
authors.lastname: Roghani
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schliebs
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.forename: Osama
authors.initials: O
authors.lastname: Sabri
mesh_terms: D000818:Animals; D001345:Autoradiography; D019817:Benzoic Acid / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D001921:Brain / Q000166:cytology / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D010078:Oxazines / Q000737:chemistry*; D016716:PC12 Cells; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D051381:Rats; D013379:Substrate Specificity; D014018:Tissue Distribution; D050494:Vesicular Acetylcholine Transport Proteins / Q000032:analysis / Q000378:metabolism*
chemical_list: D005462:Fluorine Radioisotopes; D010078:Oxazines; D050494:Vesicular Acetylcholine Transport Proteins; D019817:Benzoic Acid