Radiosynthesis of the candidate β‐amyloid radioligand [¹¹C]AZD2184: Positron emission tomography examination and metabolite analysis in cynomolgus monkeys

Beta-amyloid accumulation is associated with the pathogenesis of Alzheimer's disease (AD). AZD2184, a new radioligand for high-contrast positron emission tomography (PET) imaging of Abeta-deposits, has recently been developed and characterized in vitro and in rodents ex vivo. The objective of this study was to label AZD2184 with carbon-11, to perform in vivo characterization of [(11)C]AZD2184 ([(11)C]5) in the cynomolgus monkey brain as well as whole-body dosimetry, and to examine the metabolism of the labeled radioligand. [(11)C]5 was prepared by a two-step radiosynthesis starting with the reaction of 5-(6-(tert-butyldimethylsilyloxy)benzo[d]thiazol-2-yl)pyridin-2-amine with [(11)C]methyl iodide followed by deprotection using water. Four brain PET measurements in two cynomolgus monkeys and one whole-body PET measurement were performed with [(11)C]5. There was a high and rapid brain uptake (2.2-3.4% of injected dose at 2 min). The distribution of brain radioactivity was fairly uniform, with early to late-brain concentration ratios (peak vs. 60 min) higher for [(11)C]5 than ratios previously reported for [(11)C]PIB (8.2 and 4.6, respectively). Based on the whole-body data, it was estimated that an effective dose in an adult male would be 6.2 muSv/MBq and thus would be safe from a radiation point of view for multiple scans within the same year. [(11)C]5 shows binding characteristics, suggesting low levels of white-matter retention, and may thus provide improved contrast when compared with currently used PET radioligands for visualization of Abeta-deposits. On the basis of the labeling chemistry and the results of the biological evaluation, we conclude that [(11)C]5 should be useful for routine clinical studies.