Human Brain Imaging of α7 nAChR with [18F]ASEM: a New PET Radiotracer for Neuropsychiatry and Determination of Drug Occupancy

Using the alpha 7-nAChR radiotracer, [F-18]ASEM, we present the first successful human positron emission tomography (PET) studies. Rodent occupancy with three clinically employed alpha 7-nAChR drugs confirms the specificity of the radiotracer. Five healthy male subjects were imaged for 90 min following IV [F-18]ASEM. Two subjects were scanned for the second time (test/retest; TRV). Mouse biodistribution of [F-18]ASEM was carried out in CD1 mice injected with using human equivalent doses of DMXB-A, EVP-6124, and varenicline to block specific binding. [F-18]ASEM readily entered the brain and peaked at 15 min post-injection with reversible kinetics and a peak %SUV of about 400 %. The regional human brain distribution of [F-18]ASEM matched previous in vitro data and baboon PET results. The precuneus, parietal, occipital, cingulate cortexes, putamen, and thalamus showed high values of distribution volume (> 20 ml/ml) and binding potentials > 1 with TRV averaged 10.8 +/- 5.1 %. In mouse distribution studies, there was significant dose-dependent blockade in the mouse brain with DMXB-A as well as the other two alpha 7-nAChR drugs. The characteristics of [F-18]ASEM are consistent with the ability to quantify alpha 7-nAChR in the human brain. [F-18]ASEM is suitable for imaging neuropsychiatric disorders and target engagement (receptor occupancy) of potential alpha 7-nAChR drugs.