Identification of the allosteric P2X₇ receptor antagonist [¹¹C]SMW139 as a PET tracer of microglial activation

The P2X₇ receptor plays a significant role in microglial activation, and as a potential drug target, the P2X₇ receptor is also an interesting target in positron emission tomography. The current study aimed at the development and evaluation of a potent tracer targeting the P2X₇ receptor, to which end four adamantanyl benzamide analogues with high affinity for the human P2X₇ receptor were labelled with carbon-11. All four analogues could be obtained in excellent radiochemical yield and high radiochemical purity and molar activity, and all analogues entered the rat brain. [¹¹C]SMW139 showed the highest metabolic stability in rat plasma, and showed high binding to the hP2X₇ receptor in vivo in a hP2X₇ receptor overexpressing rat model. Although no significant difference in binding of [¹¹C]SMW139 was observed between post mortem brain tissue of Alzheimer's disease patients and that of healthy controls in in vitro autoradiography experiments, [¹¹C]SMW139 could be a promising tracer for P2X₇ receptor imaging using positron emission tomography, due to high receptor binding in vivo in the hP2X₇ receptor overexpressing rat model. However, further investigation of both P2X₇ receptor expression and binding of [¹¹C]SMW139 in other neurological diseases involving microglial activation is warranted.