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

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 [F-18]FBMV) was synthesized with an average specific activity of 75 GBq/mu mol 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. [F-18]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 PC 12 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 1921gG-saporin. [F-18]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. (C) 2009 Elsevier Inc. All rights reserved.