¹¹ C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than ¹¹ C-(R)-PK11195

Positron emission tomography (PET) radioligands for translocator protein 18 kDa (TSPO) are widely used to measure neuroinflammation, but controversy exists whether second-generation radioligands are superior to the prototypical agent ¹¹ C-(R)-PK11195 in human imaging. This study sought to quantitatively measure the “signal to background” ratio (assessed as binding potential (BP _ND )) of ¹¹ C-(R)-PK11195 compared to one of the most promising second-generation radioligands, ¹¹ C-DPA-713. Healthy subjects had dynamic PET scans and arterial blood measurements of radioligand after injection of either ¹¹ C-(R)-PK11195 (16 subjects) or ¹¹ C-DPA-713 (22 subjects). To measure the amount of specific binding, a subset of these subjects was scanned after administration of the TSPO blocking drug XBD173 (30–90 mg PO). ¹¹ C-DPA-713 showed a significant sensitivity to genotype in brain, whereas ¹¹ C-(R)-PK11195 did not. Lassen occupancy plot analysis revealed that the specific binding of ¹¹ C-DPA-713 was much greater than that of ¹¹ C-(R)-PK11195. The BP _ND in high-affinity binders was about 10-fold higher for ¹¹ C-DPA-713 (7.3) than for ¹¹ C-(R)-PK11195 (0.75). Although the high specific binding of ¹¹ C-DPA-713 suggests it is an ideal ligand to measure TSPO, we also found that its distribution volume increased over time, consistent with the accumulation of radiometabolites in brain.