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 (IC50) of the potent P-gp inhibitor tariquidar in P-gp-overexpressing cells was significantly different using either [11C]verapamil (44 nM), [11C] N-desmethyl-loperamide (19 nM) or [11C]metoclopramide (4 nM) as substrate probes. In vivo PET imaging in rats showed that the half-maximum inhibition of P-gp-mediated efflux of [11C]metoclopramide, achieved using 1 mg/kg tariquidar ( in vivo IC50 = 82 nM in plasma), increased brain exposure by 2.1-fold for [11C]metoclopramide (p < 0.05, n = 4) and 2.4-fold for [11C]verapamil (p < 0.05, n = 4), whereby cerebral uptake of the “avid” substrate [11C] 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.

Approaches to minimize the effects of P‐glycoprotein in drug transport: A review

“…The concentration of Ivermectin (87 folds) and Dexamethasone was higher in MDR1a knockout mice brain concerning wild‐type mice (Meijer et al, 1998; Schinkel et al, 1994). Uptake of [11C](R)‐RWAY 2.5–2.8 fold higher in P‐gp knockout mice brain, confirmed by PET (positron emission tomography) and tissue sampling respectively (Liow et al, 2007; Breuil et al, 2022; Bansal et al, 2009).…”

[18F]2-Fluoro-2-deoxy-sorbitol PET Imaging for Quantitative Monitoring of Enhanced Blood-Brain Barrier Permeability Induced by Focused Ultrasound

“…We have shown that FUS-induced BBB disruption did not significantly impact the efflux transport of the P-gp substrate [ 11 C]N-desmethyl-loperamide and the dual P-gp/BCRP substrate [ 11 C]erlotinib in rats [33]. These particular PET probes may however lack the sensitivity to detect subtle changes in transporter function [41]. Decrease in P-gp expression has been reported 24-48 h after FUS [42,43].…”

Parametric imaging of P-glycoprotein function at the blood-brain barrier using kE,brain-maps generated from [11C]metoclopramide PET data in rats, nonhuman primates and humans

“…Data sets [ 11 C]Metoclopramide PET data used in this analysis, obtained in different species and in different conditions, have been previously reported [11,[15][16][17]. Details on image acquisition and data analysis to generate time activity curves (TACs) in the brain are described in the corresponding articles.…”

“…Tariquidar (8 mg/kg) was i.v. injected 15 min before i.v injection of [ 11 C]metoclopramide [17]. Carbamazepine or ritonavir were used to induce or inhibit cytochrome P450 (CYP) activity, respectively.…”