The Low-Affinity Binding of Second Generation Radiotracers Targeting TSPO is Associated with a Unique Allosteric Binding Site

[11c]-pk11195 (pk11195) has been widely used with positron emission tomography (pet) to assess levels of the translocator protein 18 kda (tspo) as a marker of neuroinflammation. recent ligands, such as [11c]-pbr28 and [11c]-dpa713, have improved signal-to-noise ratio and specificity for tspo over pk11195. however, these second generation radiotracers exhibit binding differences due to a single polymorphism (rs6971) that leads to three genotypes: c/c, c/t and t/t associated with high, mixed and low binding affinities, respectively. here we report that [3h]-dpa-713 in the presence of cholesterol or pk11195 has an accelerated dissociation rate from tspo in platelets isolated from individuals with the t/t genotype. this allosteric interaction was not observed in platelets isolated from individuals with the c/c or c/t genotype. the results provide a molecular rationale for low binding affinity of t/t tspo and further support the exclusion of these subjects from pet imaging studies using second generation tspo ligands.