Synthesis and initial preclinical evaluation of the P2X7 receptor antagonist [11C]A‐740003 as a novel tracer of neuroinflammation

Neuroinflammation, in particular activation of microglia, is thought to play an important role in the progression of neurodegenerative diseases. In activated microglia, the purinergic P2X₇ receptor is upregulated. A‐740003, a highly affine and selective P2X₇ receptor antagonist, is a promising candidate for the development of a radiotracer for imaging of neuroinflammation by positron emission tomography. For this purpose, [¹¹C]A‐740003 was synthesised and evaluated in vivo with respect to both tracer metabolism and biodistribution. In plasma, a moderate metabolic rate was seen. In healthy rat brain, only marginal uptake of [¹¹C]A‐740003 was observed and, therefore, metabolites in brain could not be determined. Whether the minimal brain uptake is due to the low expression levels of the P2X₇ receptor in healthy brain or to limited transport across the blood–brain barrier has yet to be elucidated.