11C-ER176, a Radioligand for 18-kDa Translocator Protein, Has Adequate Sensitivity to Robustly Image All Three Affinity Genotypes in Human Brain

For PET imaging of 18-kDa translocator protein (TSPO), a biomarker of neuroinflammation, most second-generation radioligands are sensitive to the single nucleotide polymorphism rs6971; however, this is probably not the case for the prototypical agent C-11-PK11195 N-butan-2-yl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide), which has a relatively lower signal-to-noise ratio. We recently found that C-11-ER176 (C-11-(R)-N-sec-butyl-4-(2-chlorophenyl)-N-methylquinazoline-2-carboxamide), a new analog of C-11-(R)-PK11195, showed little sensitivity to rs6971 when tested in vitro and had high specific binding in monkey brain. This study sought, first, to determine whether the sensitivity of C-11-ER176 in humans is similar to the low sensitivity measured in vitro and, second, to measure the nondisplaceable binding potential (BPND, or the ratio of specific-to-nondisplaceable uptake) of C-11-ER176 in human brain. Methods: Nine healthy volunteers-3 high-affinity binders (HABs), 3 mixed-affinity binders (MABs), and 3 low-affinity binders (LABs)-were studied with whole body C-11-ER176 PET imaging. SUVs from 60 to 120 min after injection derived from each organ were compared between genotypes. Eight separate healthy volunteers-3 HABs, 3 MABs, and 2 LABs-under-went brain PET imaging. The 3 HABs underwent a repeated brain scan after TSPO blockade with XBD173 (N-benzyl-N-ethyl-2-(7-methyl-8-oxo-2-phenylpurin-9-yl)acetamide) to determine nondisplaceable distribution volume (V-ND) via Lassen occupancy plotting and thereby estimate BPND in brain. Results: Regional SUV averaged from 60 to 120 min after injection in brain and peripheral organs with high TSPO densities such as lung and spleen were greater in HABs than in LABs. On the basis of V-ND determined via the occupancy plot, the whole brain BPND for LABs was estimated to be 1.4 +/- 0.8, which was much lower than that for HABs (4.2 +/- 1.3) but about the same as that for HABs with C-11-PBR28 ([methyl-C-11]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine)) (similar to 1.2). Conclusion: Obvious in vivo sensitivity to rs6971 was observed in C-11-ER176 that had not been expected from in vitro studies, suggesting that the future development of any improved radioligand for TSPO should consider the possibility that in vitro properties will not be reflected in vivo. We also found that C-11-ER176 has adequately high BPND for all rs6971 genotypes. Thus, the new radioligand would likely have greater sensitivity in detecting abnormalities in patients.