Study on CHIBA-1001 as a Novel Radioligand for α7 Nicotinic Acetylcholine Receptors

Objectives The α7 nicotinic acetylcholine receptors (nAChRs) play a vital role in the pathophysiology of neuropsychiatric diseases such as Alzheimer’s disease and depression. However, there is currently no suitable positron emission tomography (PET) or single-photon emission computed tomography (SPECT) radioligands for imaging α7 nAChRs in brain. In this study, our aim is to evaluate CHIBA-1001 for in vitro binding assays and whole body biodistribution study with KM mouse.

Methods The assays of I-125-CHIBA-1006 binding to rat brain membranes were performed at 4 °C. Whole body biodistribution study was performed at different time points post injection of I-131-CHIBA-1001 in KM mice.

Results In saturation binding isotherms, nonlinear regression analysis of specific binding revealed an apparent Kd of 81.87±7.95 nM and a B max of 63.97±17.45 fmol/mg protein (n = 5, mean 6 S.E.M.) at 4℃.The liver showed the highest initial uptake followed by thelung, kidneys, small intestines, spleen, brain, and bladder. The liver and kidney uptake reached 31.69±3.64%ID/g and13.6±2.04%ID/g, respectively. Furthermore, the biodistributiondata of brain at 15, 30, and 60 min were 11.05±1.04%ID/g,8.8±0.04%ID/g and 6.28±1.13%ID/g, respectively.At 60 minthe retention of radiolabeled ligand in the brain was up to 50% ofthe 15 min uptake. Hence, the ratio of brain-to-blood and brain-to-muscle uptake after injection of131I-CHIBA-1001 were significantly higher (P<0.05), especially at 15 min.The ratio of brain-to-blood and brain-to-muscle at 15 min reached 2.7 and 3.7, respectively.

Conclusions The present study suggests that I-125-CHIBA-1001 binds with high selectivity for α7 nAChRs in the rat brain. I-131-CHIBA-1001 can be a candidate for imaging α7 acetylcholine receptors, which will be of great value for the diagnosis and treatment of mental diseases.