title: Synthesis, radiosynthesis, and biological evaluation of fluorinated thienylcyclohexyl piperidine derivatives as potential radiotracers for the NMDA receptor-linked calcium ionophore.
abstract: Various thienylcyclohexyl piperidine (TCP) derivatives were synthesized and evaluated as potential candidates for use as radiotracers for the in vivo study of the NMDA receptor ion-channel. Modification of the thienylcyclohexylpiperidine was accomplished by substituting its piperidine ring either with other cycloamine rings or N-alkyl-substituted amines, and these two classes of TCP derivatives were synthesized using two different methods. The compounds exhibited affinities ranging from 65 nM up to micromolar in competition assays for the receptor ion-channel labeled with 3H-(+)-MK-801 in rat brain homogenates. Radiosynthesis of 1-[1-(2-thienyl)-4-([18F]fluoro)-cyclohexyl]-1,2,5, 6-tetrahydropyridine was carried out by nucleophilic substitution reaction of 1-[1-(2-thienyl)-4-tosyloxycyclohexyl]-1,2,5,6-tetrahydropyridine with no carrier added 18F-, and the yield was approximately 5-10% (decay corrected) in specific activities of 500-1000 Ci/mmol after reverse-phase HPLC purification. The tracer showed good uptake in rat brains after i.v. injection (approx. 0.10% injected dose/g at 30 min. p.i.). However, the specific uptake in receptor-rich regions (striata, hippocampus, frontal cortex, and parietal cortex) improved only marginally with time compared to cerebellum. Three hours postinjection, parietal cortex showed a maximum ratio of 1.9. Preliminary PET experiment with this radiotracer in a rhesus monkey showed good uptake in the brain regions. However, little retention of the radiotracer was observed in the receptor-rich regions.
authors.affiliation: Franklin Mclean Institute, Department of Radiology, University of Chicago, IL 60637, USA.
authors.forename: X
authors.initials: X
authors.lastname: Ouyang
authors.forename: J
authors.initials: J
authors.lastname: Mukherjee
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Yang
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D015220:Calcium Channels / Q000032:analysis / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000378:metabolism; D005462:Fluorine Radioisotopes; D007202:Indicators and Reagents; D007553:Isotope Labeling / Q000379:methods; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D015220:Calcium Channels; D005462:Fluorine Radioisotopes; D007202:Indicators and Reagents; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; C012058:tenocyclidine; D010622:Phencyclidine