Blockade of translocator protein (TSPO) to measure specific binding of C-11-(R)-PK 11195 in human brain

467 Objectives Controversy remains about the percentage of 11C-(R)-PK 11195 uptake in human brain that is specifically bound to translocator protein (TSPO) and whether its in vivo binding is affected by the co-dominantly expressed polymorphism rs6971. The purpose of this study is to measure binding potential (BPND, the ratio of specific to nondisplaceable uptake) of 11C-(R)-PK 11195 in human brain after partial blockade of TSPO by XBD173, a TSPO agonist, in each of the three genotypes. Methods Eight healthy humans (4 high- (HABs), 2 mixed- (MABs), and 2 low-affinity binders (LABs)) had two 11C-(R)-PK 11195 scans: baseline and after oral administration of XBD173 (45-90 mg). Total distribution volume (VT) was measured by Logan plot in the baseline scan, and nondisplaceable distribution volume (VND) was measured by the Lassen plot for the two scans. Results VT in the baseline scans was similar among the three genotypes: 0.74 (HABs), 0.74 (MABs), and 0.66 (LABs). After XBD173 administration, VT decreased about 15% in both HABs and MABs, but was unchanged in LABs. From the blocked scans, VND was calculated to be 0.54 (HABs) and 0.49 (MABs), with that in LABs being indeterminable. BPND was 0.39 (HABs) and 0.47 (MABs). However, XBD173 increased the plasma free fraction (fP) of radioligand by an average of 19% in six of the eight subjects, but with a decrease in one HAB and one LAB. By correcting VT and VND for fP, the resulting BPND increased ~130% both in HABs (from 0.39 to 0.89) and in MABs (from 0.52 to 1.22). Conclusions Depending on whether the imaging results are corrected for the increase of fP apparently caused by XBD173, the BPND of 11C-(R)-PK 11195 in human brain of both HABs and MABs was either low (~0.4 without correction) or moderate (~1.0 with correction). The effect, if any, of genotype may be difficult to detect with this blockade paradigm, as the lack of effect of XBD173 in the LABs could be caused by decreased affinity of either the radioligand or XBD173 itself.