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 ([(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.
Sorger
Dietlind
D
Department of Nuclear Medicine, University of Leipzig, Leipzig 04103, Germany. sord@medizin.uni-leipzig.de
Scheunemann
Matthias
M
Vercouillie
Johnny
J
Grossmann
Udo
U
Fischer
Steffen
S
Hiller
Achim
A
Wenzel
Barbara
B
Roghani
Ali
A
Schliebs
Reinhard
R
Steinbach
Jörg
J
Brust
Peter
P
Sabri
Osama
O
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*
D005462:Fluorine Radioisotopes; D010078:Oxazines; D050494:Vesicular Acetylcholine Transport Proteins; D019817:Benzoic Acid