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 ([¹⁸F]FBMV) was synthesized with an average specific activity of 75 GBq/μmol 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. [¹⁸F]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 σ_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.

[¹⁸F]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.

Keywords: Vesamicol derivatives, Radiosynthesis, Rat brain, Affinity, Selectivity, VAChT, Biodistribution, Cholinergic deficiency