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Comparative vulnerability of PET radioligands to partial inhibition of P-glycoprotein at the blood-brain barrier: A criterion of choice?

Abstract : Only partial deficiency/inhibition of P-glycoprotein (P-gp, ABCB1) function at the blood-brain barrier (BBB) is likely to occur in pathophysiological situations or drug-drug interactions. This raises questions regarding the sensitivity of available PET imaging probes to detect moderate changes in P-gp function at the living BBB. $In\ vitro$, the half-maximum inhibitory concentration (IC$_{50}$ ) of the potent P-gp inhibitor tariquidar in P-gp-overexpressing cells was significantly different using either [$^{11}$C] verapamil (44 nM), [$^{11}$C]N-desmethyl-loperamide ($^{19}$ nM) or [$^{11}$C]metoclopramide (4 nM) as substrate probes. $In\ vivo$ PET imaging in rats showed that the half-maximum inhibition of P-gp-mediated efflux of [ 11 C]metoclopramide, achieved using 1 mg/kg tariquidar ( $in\ vivo$ IC$_{50}$ = 82 nM in plasma), increased brain exposure by 2.1-fold for [$^{11}$C]metoclopramide (p < 0.05, n = 4) and 2.4-fold for [$^{11}$C]verapamil (p < 0.05, n = 4), whereby cerebral uptake of the “avid” substrate [$^{11}$C] N-desmethyl-loperamide was unaffected (p > 0.05, n = 4). This comparative study points to differences in the “vulnerability” to P-gp inhibition among radiolabeled substrates, which were apparently unrelated to their “avidity” (maximal response to P-gp inhibition). Herein, we advocate that partial inhibition of transporter function, in addition to complete inhibition, should be a primary criterion of evaluation regarding the sensitivity of radiolabeled substrates to detect moderate but physiologically-relevant changes in transporter function $in\ vivo$.
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Submitted on : Monday, September 27, 2021 - 5:57:38 PM
Last modification on : Thursday, September 30, 2021 - 3:36:23 AM

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Louise Breuil, Solène Marie, Sébastien Goutal, Sylvain Auvity, Charles Truillet, et al.. Comparative vulnerability of PET radioligands to partial inhibition of P-glycoprotein at the blood-brain barrier: A criterion of choice?. Journal of Cerebral Blood Flow and Metabolism, Nature Publishing Group, inPress, pp.0271678X2110454. ⟨10.1177/0271678X211045444⟩. ⟨cea-03356224⟩

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