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

Abstract 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 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 (330–403 GBq/μmol) and radiochemical purity > 95%. Dissection studies with [ 11 C]A-833834 demonstrated low specific α7-nAChR binding in the mouse brain. [ 11 C]A-752274 specifically (~ 50%) labeled α7-nAChR in the mouse thalamus. However, [ 11 CA-752274 exhibited low brain uptake in baboon (%SUV  Conclusion Two novel α7-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 α7-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 α7-nAChR PET radioligands will be based on compounds with high binding affinities and good blood–brain barrier permeability.