Synthesis and biodistribution of radiolabeled α7 nicotinic acetylcholine receptor ligands

Martin G. Pomper, Eifion Phillips, Hong Fan, Dennis J. McCarthy, Richard A. Keith, John C. Gordon, Ursula Scheffel, Robert F. Dannals, John L. Musachio

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40 Scopus citations


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 disutfide precursor and reaction with 11C-iodomethane. N-(R)-1-Aza-bicyclo[2.2.2]oct-3-yl-4- 125]-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 unlabeted precursor or nicotine. Results: We synthesized 4 radiolabeled, moderate- to high-affinity, α7-nAChR-based ligands. The compounds were a series of quinudidine 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.

Original languageEnglish (US)
Pages (from-to)326-334
Number of pages9
JournalJournal of Nuclear Medicine
Issue number2
StatePublished - 2005


  • C
  • I
  • PET
  • Spirofuropyridine
  • α nicotinic receptor

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging


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