[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.

Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine Baltimore MD USA

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague Czech Republic

Johns Hopkins Drug Discovery Johns Hopkins University School of Medicine 855 North Wolfe Street Office 230 Baltimore MD 21205 USA

Molecular and Comparative Pathobiology Johns Hopkins University School of Medicine Baltimore MD USA

Neurology Psychiatry Neuroscience Medicine and Oncology Johns Hopkins University School of Medicine Baltimore MD USA

Russell H Morgan Department of Radiology and Radiological Science Johns Hopkins University School of Medicine Baltimore MD USA

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