Synthesis and evaluation of new radioligands [11C]A-833834 and [11C]A-752274 for positron-emission tomography of α7-nicotinic acetylcholine receptors

Andrew G. Horti, Hayden T Ravert, Yongjun Gao, Daniel P. Holt, William H. Bunnelle, Michael R. Schrimpf, Tao Li, Jianguo Ji, Heather Valentine, Ursula Scheffel, Hiroto Kuwabara, Dean Foster Wong, Robert F. Dannals

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Introduction: α7-nicotinic acetylcholine receptor (α7-nAChR) is one of the major neuronal nAChR subtypes. α7-nAChR is involved in variety of neuronal processes and disorders including schizophrenia and Alzheimer's disease. A number of α7-nAChR PET radioligands have been developed, but a quality radiotracer remains to be discovered. Methods: High binding affinity α7-nAChR ligands A-833834 and A-752274 were radiolabeled with 11C. Baseline and blockade biodistribution studies in the mouse brain of [11C]A-833834 (5-(6-(5-[11C]methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-1H-indole) and [11C]A-752274 (2-(6-[11C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-7-(6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-9H-fluoren-9-one) were performed. [11C]A-752274 was evaluated in a baseline baboon PET study. Results: [11C]A-833834 and [11C]A-752274 were synthesized by radiomethylation of corresponding des-methyl precursors. The radioligands were prepared with radiochemical yield of 12%-32%, high specific radioactivity (330-403GBq/μmol) and radiochemical purity>95%. Dissection studies with [11C]A-833834 demonstrated low specific α7-nAChR binding in the mouse brain. [11C]A-752274 specifically (~50%) labeled α7-nAChR in the mouse thalamus. However, [11CA-752274 exhibited low brain uptake in baboon (%SUV<100). Conclusion: Two novel α7-nAChR ligands radioligands were synthesized and studied in animals. Specific binding of [11C]A-833834 in the mouse brain is low due to the insufficient binding affinity of the radioligand. The very high binding affinity [11C]A-752274 exhibited good specific binding in the α7-nAChR-rich mouse brain regions. The low uptake of [11C]A-752274 in the baboon brain is due to its high hydrophilicity, rapid metabolism or other properties. Future development of α7-nAChR PET radioligands will be based on compounds with high binding affinities and good blood-brain barrier permeability.

Original languageEnglish (US)
Pages (from-to)395-402
Number of pages8
JournalNuclear Medicine and Biology
Issue number3
StatePublished - Apr 2013


  • Nicotinic acetylcholine receptor
  • PET
  • Positron emission tomography
  • Radioligand
  • α7-nAChR

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Cancer Research


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