¹¹C‐ and ¹⁸F‐Labeled Radioligands for P‐Glycoprotein Imaging by Positron Emission Tomography

Abstract

P-Glycoprotein (P-gp) is an efflux transporter widely expressed at the human blood-brain barrier. It is involved in xenobiotics efflux and in onset and progression of neurodegenerative disorders. For these reasons, there is great interest in the assessment of P-gp expression and function by noninvasive techniques such as positron emission tomography (PET). Three radiolabeled aryloxazole derivatives: 2-[2-(2-methyl-((11)C)-5-methoxyphenyl)oxazol-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ([(11)C]-5); 2-[2-(2-fluoromethyl-((18)F)-5-methoxyphenyl)oxazol-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetra-hydroisoquinoline ([(18)F]-6); and 2-[2-(2-fluoroethyl-((18)F)-5-methoxyphenyl)oxazol-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ([(18)F]-7), were tested in several in vitro biological assays to assess the effect of the aryl substituent in terms of potency and mechanism of action toward P-gp. Methyl derivative [(11)C]-5 is a potent P-gp substrate, whereas the corresponding fluoroethyl derivative [(18)F]-7 is a P-gp inhibitor. Fluoromethyl compound [(18)F]-6 is classified as a non-transported P-gp substrate, because its efflux increases after cyclosporine A modulation. These studies revealed a promising substrate and inhibitor, [(11)C]-5 and [(18)F]-7, respectively, for in vivo imaging of P-gp by using PET.

Positron emission tomography imaging sheds new light on hypoxia and antitumor therapies

“…While most P‐gp locates on the blood‐brain barrier, 144 it is also widely expressed on cell membranes of the kidney, liver, and intestines 145 . There are various PET agents that target P‐gp to measure its function, some of which have been used in humans, such as 11 C‐verapamil and 11 C‐loperamide 126 . However, many current PET probes targeting P‐gp are mainly substrates or inhibitors of P‐gp, and the main challenges to overcome are achieving high selectivity for P‐gp and minimal radiometabolites to ensure accurate measurement of P‐gp function and to investigate whether P‐gp inhibitors can improve MDR 144 .…”

“…145 There are various PET agents that target P-gp to measure its function, some of which have been used in humans, such as 11 C-verapamil and 11 Cloperamide. 126 However, many current PET probes targeting P-gp are mainly substrates or inhibitors of P-gp, and the main challenges to overcome are achieving high selectivity for P-gp and minimal radiometabolites to ensure accurate measurement of P-gp function and to investigate whether P-gp inhibitors can improve MDR. 144 Therefore, if the relationship between hypoxia and P-gp expression and chemoresistance can be clarified, it is expected to improve chemotherapy efficacy by addressing hypoxia.…”

Mechanisms and the clinical relevance of complex drug–drug interactions

“… 47 In humans, the most convincing evidence of Pgp-mediated drug transport comes from PET studies with potent Pgp inhibitor tariquidar. 48 , 51 , 52 This inhibitor was shown to increase brain penetration of verapamil, loperamide and a loperamide metabolite. 48 , 51 , 52 In a group of healthy individuals, tariquidar increased the apparent brain volume distribution of the cardiovascular drug verapamil.…”