Comparative vulnerability of PET radioligands to partial inhibition of P-glycoprotein at the blood-brain barrier: A criterion of choice?. Issue 1 (January 2022)

• Record Type: Journal Article
• Authors: Breuil, Louise; Marie, Solène; Goutal, Sébastien; Auvity, Sylvain; Truillet, Charles; Saba, Wadad; Langer, Oliver; Caillé, Fabien; Tournier, Nicolas
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 42:Issue 1(2022)
• Page Start: 175
• Page End: 185
• Publication Date: 2022-01
• Subjects: ATP-binding cassette -- drug-drug interaction -- membrane transporter -- neuropharmacology -- pharmacokinetics; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1177/0271678X211045444
• Languages: English
• ISSNs: 0271-678X

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 (IC50 ) 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 IC50 = 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 .