PET imaging of high-affinity a4b2 nicotinic acetylcholine receptors in humans with 18F-AZAN, a radioligand with optimal brain kinetics

Dean F. Wong, Hiroto Kuwabara, Jongho Kim, James R. Brašić, Wichana Chamroonrat, Yongjun Gao, Heather Valentine, William Willis, Anil Mathur, Mary E. McCaul, Gary Wand, Emily G. Gean, Robert F. Dannals, Andrew G. Horti

Research output: Contribution to journalArticle

Abstract

We evaluated (2)-2-(6-[18F]fluoro-2,39-bipyridin-59-yl)-7- methyl- 7-aza-bicyclo[2.2.1]heptane (18F-AZAN), a novel radiotracer that binds to a4b2 nicotinic acetylcholine receptors (a4b2-nAChRs) and shows high specific binding and rapid and reversible kinetics in the baboon and human brain. Methods: We tested safety tolerability and test-retest reliability (n = 5) and proposed initial quantification of 18F-AZAN receptors in 3 healthy human subjects who had nicotine exposure and 9 who did not. We also present a receptor blocking study in a nicotine subject dosed with the a4b2-nAChR- selective partial agonist varenicline. Results: Radiation dosimetry PET/CT experiments indicated that most human organs received doses between 0.008 and 0.015 mSv/MBq, with an effective dose of approximately 0.014 mSv/MBq. The tracer rapidly entered the brain, and the peak was reached before 20 min, even for thalamus. Ninety-minute scans were sufficient for 18F-AZAN to obtain the ratio at equilibrium of specifically bound radioligand to nondisplaceable radioligand in tissue (BPND) using plasma reference graphical analysis, which showed excellent reproducibility of BPND (test-retest variability < 10%) in the nAChR-rich brain regions. Regional plasma reference graphical analysis BPND values exceeded 2 in the midbrain tegmental nuclei, lateral geniculate body, and thalamus for nonsmokers (n = 9) but were less than 1 in the nAChR-poor brain regions. There was a dramatic reduction of 18F-AZAN brain uptake in smokers and varenicline-treated subjects. Conclusion: 18FAZAN is a highly specific, safe, and effective PET radioligand for human subjects that requires only 90 min of PET scanning to estimate high-affinity a4b2-nAChR in the living human brain. COPYRIGHT

Original languageEnglish (US)
Pages (from-to)1308-1314
Number of pages7
JournalJournal of Nuclear Medicine
Volume54
Issue number8
DOIs
StatePublished - Aug 1 2013

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Keywords

  • Human neuroimaging
  • Nicotinic receptors
  • PET

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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