RT Journal Article SR Electronic T1 Synthesis and Biodistribution of Radiolabeled α7 Nicotinic Acetylcholine Receptor Ligands JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 326 OP 334 VO 46 IS 2 A1 Martin G. Pomper A1 Eifion Phillips A1 Hong Fan A1 Dennis J. McCarthy A1 Richard A. Keith A1 John C. Gordon A1 Ursula Scheffel A1 Robert F. Dannals A1 John L. Musachio YR 2005 UL http://jnm.snmjournals.org/content/46/2/326.abstract AB Our objective was to develop an array of α7-selective nicotinic cholinergic receptor (nAChR)–based imaging agents for PET and SPECT. Methods: (2′R)-N-11C-Methyl-N-(phenylmethyl)-spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridin]-5′-amine 1 was synthesized by reaction of the corresponding desmethyl precursor with 11C-CO2 and reduction. N-(R)-1-Aza-bicyclo[2.2.2]oct-3-yl-4-11C-methylsulfanyl-benzamide 2 was synthesized by reduction of the corresponding disulfide precursor and reaction with 11C-iodomethane. N-(R)-1-Aza-bicyclo[2.2.2]oct-3-yl-4-125I-iodo-benzamide 3 was synthesized by halogen exchange of the corresponding bromide. (2′R)-5′-(2-125I-iodo-3-furanyl)spiro[1-azabicyclo[2.2.2]octane]-3,2′(3′H)-furo[2,3-b]pyridine 4 was synthesized by the chloramine-T method. Kinetic biodistribution studies were done in male CD-1 mice by tail vein injection of 3.7 MBq (100 μCi) of the 11C-labeled radiotracer or 0.67 MBq (2 μCi) of the 125I-labeled radiotracer followed by brain dissection and tissue counting. Receptor blockade was determined by pretreatment of the mice with an excess of either unlabeled precursor or nicotine. Results: We synthesized 4 radiolabeled, moderate- to high-affinity, α7-nAChR–based ligands. The compounds were a series of quinuclidine derivatives with an inhibition constant (Ki) < 6 nmol/L (33 pmol/L for 4) for α7-nAChR and selectivities of α7/α4β2 subtypes of ≥14,000. All of the compounds were produced in adequate radiochemical yield and specific radioactivity (>74 GBq/μmol [2,000 Ci/mmol]). No site selectivity or receptor blockade was shown for 1 and 2 (0.91 ± 0.05 and 0.14 ± 0.03 %ID/g [percentage injected dose per gram] in the hippocampus [target tissue], respectively). Compound 3 showed low hippocampal uptake (0.25 ± 0.05 %ID/g) but prolonged retention within that structure. Pretreatment with nicotine decreased its uptake by up to 50% in the hippocampus. Similar reductions were also observed within the cerebellum (nontarget tissue). Compound 4 showed hippocampal uptake of 2.41 ± 0.03 %ID/g and target-to-nontarget uptake ratios of up to 2. Pretreatment of animals with unlabeled 4 resulted in a decrease of hippocampal uptake to 60% of its preblockade value without a corresponding decrease in cerebellar uptake. Conclusion: With further structural optimization, selective imaging of α7-nAChR may be possible.