Two Binding Sites for 3 HPBR28 in Human Brain: Implications for TSPO PET Imaging of Neuroinflammation

(11)CPBR28, a radioligand targeting the translocator protein (TSPO), does not produce a specific binding signal in approximately 14% of healthy volunteers. This phenomenon has not been reported for (11)CPK11195, another TSPO radioligand. We measured the specific binding signals with (3)HPK11195 and (3)HPBR28 in brain tissue from 22 donors. Overall, 23% of the samples did not generate a visually detectable specific autoradiographic signal with (3)HPBR28, although all samples showed (3)HPK11195 binding. There was a marked reduction in the affinity of (3)HPBR28 for TSPO in samples with no visible (3)HPBR28 autoradiographic signal (K(i)=188+/-15.6 nmol/L), relative to those showing normal signal (K(i)=3.4+/-0.5 nmol/L, P<0.001). Of this latter group, (3)HPBR28 bound with a two-site fit in 40% of cases, with affinities (K(i)) of 4.0+/-2.4 nmol/L (high-affinity site) and 313+/-77 nmol/L (low-affinity site). There was no difference in K(d) or B(max) for (3)HPK11195 in samples showing no (3)HPBR28 autoradiographic signal relative to those showing normal (3)HPBR28 autoradiographic signal. (3)HPK11195 bound with a single site for all samples. The existence of three different binding patterns with PBR28 (high-affinity binding (46%), low-affinity binding (23%), and two-site binding (31%)) suggests that a reduction in (11)CPBR28 binding may not be interpreted simply as a reduction in TSPO density. The functional significance of differences in binding characteristics warrants further investigation.