Two binding sites for [3H]PBR28 in human brain: implications for TSPO PET imaging of neuroinflammation

[C-11] PBR28, 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 [C-11] PK11195, another TSPO radioligand. We measured the specific binding signals with [H-3] PK11195 and [H-3] PBR28 in brain tissue from 22 donors. Overall, 23% of the samples did not generate a visually detectable specific autoradiographic signal with [H-3] PBR28, although all samples showed [H-3] PK11195 binding. There was a marked reduction in the affinity of [H-3] PBR28 for TSPO in samples with no visible [H-3] PBR28 autoradiographic signal (K-i = 188 +/- 15.6nmol/L), relative to those showing normal signal (K-i = 3.4 +/- 0.5 nmol/L, P < 0.001). Of this latter group, [H-3] PBR28 bound with a two-site fit in 40% of cases, with affinities (Ki) of 4.0 +/- 2.4 nmol/L (high-affinity site) and 313 +/- 77nmol/L (low-affinity site). There was no difference in K-d or B-max for [H-3] PK11195 in samples showing no [H-3] PBR28 autoradiographic signal relative to those showing normal [H-3] PBR28 autoradiographic signal. [H-3] PK11195 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 [C-11] PBR28 binding may not be interpreted simply as a reduction in TSPO density. The functional significance of differences in binding characteristics warrants further investigation. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 1608-1618; doi:10.1038/jcbfm.2010.63; published online 28 April 2010