Abstract
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.
Highlights
The P2X7 receptor plays a significant role in microglial activation, and as a potential drug target, the P2X7 receptor is an interesting target in positron emission tomography
P2X7 receptor (P2X7R) is emerging as a target in positron emission tomography (PET), with four radiolabelled antagonists reported to date[4,5,6,7,8,9]
As for the fluorinated adamantanyl analogues, demethylation using boron tribromide would lead to trans-halogenation of the fluorine, analogues 6–8 were synthesised in good yields (73–79%) via a chemoselective coupling of 2-chloro-5-hydroxybenzoic acid 12 and the appropriate adamantanemethylamine (9–11, Fig. 1)
Summary
The P2X7 receptor plays a significant role in microglial activation, and as a potential drug target, the P2X7 receptor is 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. 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. Further investigation of both P2X7 receptor expression and binding of [11C]SMW139 in other neurological diseases involving microglial activation is warranted. To assess the potential of [11C]SMW139 in a clinical setting, in vitro autoradiography studies on post mortem brain material of AD patients were performed, including extensive immunohistochemical staining
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