HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH RSS TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JNM Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pomper, M. G. Articles by Musachio, J. L. Search for Related Content PubMed PubMed Citation Articles by Pomper, M. G. Articles by Musachio, J. L.

Synthesis and Biodistribution of Radiolabeled ₇ Nicotinic Acetylcholine Receptor Ligands

¹ Johns Hopkins University, Baltimore, Maryland
² AstraZeneca, Wilmington, Delaware

Our objective was to develop an array of ₇-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, ₇-nAChR–based ligands. The compounds were a series of quinuclidine derivatives with an inhibition constant (K_i) < 6 nmol/L (33 pmol/L for 4) for ₇-nAChR and selectivities of ₇/₄ß₂ 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 ₇-nAChR may be possible.

Key Words: ₇ nicotinic receptor • spirofuropyridine • ¹¹C • ¹²⁵I • PET • SPECT

Related articles in JNM:

THIS MONTH IN JNM

JNM 2005 46: 8a-9a. [Full Text]