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 F. 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
Externally publishedYes


  • 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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