Synthesis and evaluation of new radioligands [(11)C]A-833834 and [(11)C]A-752274 for positron-emission tomography of a7-nicotinic acetylcholine receptors.

Nuclear medicine and biology

PubMedID: 23294899

Horti AG, Ravert HT, Gao Y, Holt DP, Bunnelle WH, Schrimpf MR, Li T, Ji J, Valentine H, Scheffel U, Kuwabara H, Wong DF, Dannals RF. Synthesis and evaluation of new radioligands [(11)C]A-833834 and [(11)C]A-752274 for positron-emission tomography of a7-nicotinic acetylcholine receptors. Nucl Med Biol. 2013;40(3):395-402.
INTRODUCTION
a7-nicotinic acetylcholine receptor (a7-nAChR) is one of the major neuronal nAChR subtypes. a7-nAChR is involved in variety of neuronal processes and disorders including schizophrenia and Alzheimer's disease. A number of a7-nAChR PET radioligands have been developed, but a quality radiotracer remains to be discovered.

METHODS
High binding affinity a7-nAChR ligands A-833834 and A-752274 were radiolabeled with (11)C. Baseline and blockade biodistribution studies in the mouse brain of [(11)C]A-833834 (5-(6-(5-[(11)C]methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-1H-indole) and [(11)C]A-752274 (2-(6-[(11)C]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. [(11)C]A-752274 was evaluated in a baseline baboon PET study.

RESULTS
[(11)C]A-833834 and [(11)C]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/┬Ámol) and radiochemical purity>95%. Dissection studies with [(11)C]A-833834 demonstrated low specific a7-nAChR binding in the mouse brain. [(11)C]A-752274 specifically (~50%) labeled a7-nAChR in the mouse thalamus. However, [(11)CA-752274 exhibited low brain uptake in baboon (%SUV<100).

CONCLUSION
Two novel a7-nAChR ligands radioligands were synthesized and studied in animals. Specific binding of [(11)C]A-833834 in the mouse brain is low due to the insufficient binding affinity of the radioligand. The very high binding affinity [(11)C]A-752274 exhibited good specific binding in the a7-nAChR-rich mouse brain regions. The low uptake of [(11)C]A-752274 in the baboon brain is due to its high hydrophilicity, rapid metabolism or other properties. Future development of a7-nAChR PET radioligands will be based on compounds with high binding affinities and good blood-brain barrier permeability.