No abstract

Purpose Using the α7-nAChR radiotracer, [18F]ASEM, we present the first successful human positron emission tomography (PET) studies. Rodent occupancy with three clinically employed α7-nAChR drugs confirms the specificity of the radiotracer. Procedures Five healthy male subjects were imaged for 90 min following IV [18F]ASEM. Two subjects were scanned for the second time (test/retest; TRV). Mouse biodistribution of [18F]ASEM was carried out in CD1 mice injected with using human equivalent doses of DMXB-A, EVP-6124, and varenicline to block specific binding. Results [18F]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 [18F]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 α7-nAChR drugs. Conclusions The characteristics of [18F]ASEM are consistent with the ability to quantify α7-nAChR in the human brain. [18F]ASEM is suitable for imaging neuropsychiatric disorders and target engagement (receptor occupancy) of potential α7-nAChR drugs.

C-RO-963, C-RO-643, andF-RO-948 (previously referred to as C-RO6924963,C-RO6931643, and F-RO6958948, respectively) have been reported as promising PET tracers for tau imaging based on in vitro and preclinical PET data. Here we describe the first, to our knowledge, human evaluation of these novel radiotracers. Amyloid PET-positive Alzheimer disease (AD) subjects and younger controls each received 2 different tau tracers. Dynamic 90-min scans were obtained after bolus injection of C-RO-963,C-RO-643, or F-RO-948. Arterial blood sampling was performed on 11 healthy controls and 11 AD subjects. Regions were defined on MR images, and PET data were quantified by plasma reference graphical analysis (for total distribution volume) and target cerebellum ratio (SUV ratios of 60- to 90-min frames). SUV ratio images were also analyzed voxelwise. Five older controls each underwent 2 scans withF-RO-948 for evaluation of test-retest variability. Four AD subjects underwent a repeated F-RO-948 scan 6-22 mo after the first scan. Six additional healthy controls (3 men and 3 women; age range, 41-67 y) each underwent 1 whole-body dosimetry scan withF-RO-948. In younger controls, SUV was observed in the temporal lobe with values of approximately 3.0 for C-RO-963, 1.5 forC-RO-643, and 3.5 for F-RO-948. Over all brain regions and subjects, the trend was forF-RO-948 to have the highest SUV, followed by C-RO-963 and thenC-RO-643. Regional analysis of SUV ratio and total distribution volume for C-RO-643 andF-RO-948 clearly discriminated the AD group from the healthy control groups. Compartmental modeling confirmed that C-RO-643 had lower brain entry than eitherC-RO-963 or F-RO-948 and thatF-RO-948 showed better contrast between (predicted) areas of high versus low tau accumulation. Thus, our subsequent analysis focused on F-RO-948. Both voxelwise and region-based analysis ofF-RO-948 binding in healthy controls versus AD subjects revealed multiple areas where AD subjects significantly differed from healthy controls. Of 22 high-binding regions, 13 showed a significant group difference (after ANOVA, = 45, < 10). Voxelwise analysis also revealed a set of symmetric clusters where AD subjects had higher binding than healthy controls (threshold of < 0.001, cluster size > 50). F-RO-948 demonstrates characteristics superior toC-RO-643 and C-RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties ofF-RO-948 compare favorably with other existing tau PET tracers.