(R)-[11C]Emopamil as a novel tracer for imaging enhanced P-glycoprotein function

Toyohara, Jun; Okamoto, Mayumi; Aramaki, Hiroki; Zaitsu, Yuto; Shimizu, Isao; Ishiwata, Kiichi

doi:10.1016/j.nucmedbio.2015.09.001

Cited by 4 publications

(4 citation statements)

References 31 publications

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“…Therefore, attempts have been made to come up with improved radiotracers to image P‐gp function at the BBB. One strategy is the use of weak P‐gp substrates, which are hypothesized to be more sensitive to detect small changes in P‐gp function at the BBB than strong substrates …”

Section: Use Of Pet To Study Drug‐transporter Interactionsmentioning

confidence: 99%

“…One strategy is the use of weak P-gp substrates, which are hypothesized to be more sensitive to detect small changes in P-gp function at the BBB than strong substrates. [47][48][49][50] Apart from the BBB, a number of radiotracers have been reported to visualize drug transporters in the liver (Table 1). 5,32,33 However, because there is usually an interplay between several different uptake transporters in the basolateral membrane and efflux transporters in the canalicular membrane of hepatocytes for the hepatic handling of a given drug, with partly overlapping substrate specificities, and because the liver is the main metabolizing organ, which often produces radiolabeled metabolites, the interpretation of transporter PET results may be more complex for the liver than for the brain.…”

Section: Use Of Pet To Study Drug-transporter Interactionsmentioning

confidence: 99%

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Use of PET Imaging to Evaluate Transporter‐Mediated Drug‐Drug Interactions

Langer

2016

The Journal of Clinical Pharma

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Several membrane transporters belonging to the adenosine triphosphate-binding cassette (ABC) and solute carrier (SLC) families can transport drugs and drug metabolites and thereby exert an effect on drug absorption, distribution, and excretion, which may potentially lead to transportermediated drug-drug interactions (DDIs). Some transporter-mediated DDIs may lead to changes in organ distribution of drugs (eg, brain, liver, kidneys) without affecting plasma concentrations. Positron emission tomography (PET) is a noninvasive imaging method that allows studying of the distribution of radiolabeled drugs to different organs and tissues and is therefore the method of choice to quantitatively assess transporter-mediated DDIs on a tissue level. There are 2 approaches to how PET can be used in transporter-mediated DDI studies. When the drug of interest is a potential perpetrator of DDIs, it may be administered in unlabeled form to assess its influence on tissue distribution of a generic transporter-specific PET tracer (probe substrate). When the drug of interest is a potential victim of DDIs, it may be radiolabeled with carbon-11 or fluorine-18 and used in combination with a prototypical transporter inhibitor (eg, rifampicin). PET has already been used both in preclinical species and in humans to assess the effects of transporter-mediated DDIs on drug disposition in different organ systems, such as brain, liver, and kidneys, for which examples are given in the present review article. Given the growing importance of membrane transporters with respect to drug safety and efficacy, PET is expected to play an increasingly important role in future drug development.

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Section: Use Of Pet To Study Drug‐transporter Interactionsmentioning

confidence: 99%

Section: Use Of Pet To Study Drug-transporter Interactionsmentioning

confidence: 99%

Use of PET Imaging to Evaluate Transporter‐Mediated Drug‐Drug Interactions

Langer

2016

The Journal of Clinical Pharma

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“…For these reasons, many efforts have been made to develop new P-gp tracers with improved pharmacokinetic properties and lower affinity to the P-gp transporter [ 25 ]. [ 11 C]metoclopramide [ 31 ], [ 11 C]emopamil [ 32 ], [ 11 C]phenytoin [ 26 ], and [ 18 F]MC225 [ 33 ] were identified as weak substrates of the P-gp transporter, showing higher tracer uptake in the brain than ( R )-[ 11 C]verapamil at baseline conditions when P-gp is functioning adequately. [ 18 F]MC225 was selected as the most promising fluorine-18 labeled tracer for in vivo measurement of P-gp function [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

Head-to-head comparison of (R)-[11C]verapamil and [18F]MC225 in non-human primates, tracers for measuring P-glycoprotein function

García-Varela

García

Aguiar³

et al. 2021

Eur J Nucl Med Mol Imaging

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Purpose P-glycoprotein (P-gp) function is altered in several brain disorders; thus, it is of interest to monitor the P-gp function in vivo using PET. (R)-[11C]verapamil is considered the gold standard tracer to measure the P-gp function; however, it presents some drawbacks that limit its use. New P-gp tracers have been developed with improved properties, such as [18F]MC225. This study compares the characteristics of (R)-[11C]verapamil and [18F]MC225 in the same subjects. Methods Three non-human primates underwent 4 PET scans: 2 with (R)-[11C]verapamil and 2 with [18F]MC225, at baseline and after P-gp inhibition. The 30-min PET data were analyzed using 1-Tissue Compartment Model (1-TCM) and metabolite-corrected plasma as input function. Tracer kinetic parameters at baseline and after inhibition were compared. Regional differences and simplified methods to quantify the P-gp function were also assessed. Results At baseline, [18F]MC225 VT values were higher, and k2 values were lower than those of (R)-[11C]verapamil, whereas K1 values were not significantly different. After inhibition, VT values of the 2 tracers were similar; however, (R)-[11C]verapamil K1 and k2 values were higher than those of [18F]MC225. Significant regional differences between tracers were found at baseline, which disappeared after inhibition. The positive slope of the SUV-TAC was positively correlated to the K1 and VT of both tracers. Conclusion [18F]MC225 and (R)-[11C]verapamil show comparable sensitivity to measure the P-gp function in non-human primates. Moreover, this study highlights the 30-min VT as the best parameter to measure decreases in the P-gp function with both tracers. [18F]MC225 may become the first radiofluorinated tracer able to measure decreases and increases in the P-gp function due to its higher baseline VT.

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“…For these reasons, many efforts have been made to develop new P-gp tracers with improved pharmacokinetic properties and lower a nity to the P-gp transporter [25]. [ 11 C]metoclopramide [31], [32], [ 11 C]phenytoin [26], and [ 18 F]MC225 [33] were identi ed as weak substrates of the Pgp transporter, showing higher tracer uptake in the brain than (R)-[ 11 C]verapamil at baseline conditions when P-gp is functioning adequately. [ 18 F]MC225 was selected as the most promising uorine-18 labeled tracer for in vivo measurement of P-gp function [34].…”

Section: Introductionmentioning

confidence: 99%

Head to head comparison of (R)-[11C]verapamil and [18F]MC225 in non-human primates, tracers for measuring P-glycoprotein function

Varela

García

Aguiar

et al. 2021

Preprint

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Purpose P-glycoprotein (P-gp) function is altered in several brain disorders; thus, it is of interest to monitor the P-gp function in vivo using PET. (R)-[11C]verapamil is considered as the gold standard tracer to measure the P-gp function, however, it presents some drawbacks that limit its use. New P-gp tracers have been developed with improved properties, such as [18F]MC225. This study compares the characteristics of (R)-[11C]verapamil and [18F]MC225 in the same subjects. Methods Three non-human primates underwent 4 PET scans: 2 with (R)-[11C]verapamil and 2 with [18F]MC225, at baseline and after P-gp inhibition. The 30-min PET data were analyzed using 1-TCM and metabolite-corrected-plasma as input function. Tracer kinetic parameters at baseline and after-inhibition were compared. Regional differences and simplified methods to quantify the P-gp function were also assessed. Results At baseline, [18F]MC225 VT values were higher and k2 values were lower than those of (R)-[11C]verapamil, whereas K1 values were not significantly different. After-inhibition, VT values of the 2 tracers were similar, however, (R)-[11C]verapamil K1 and k2 values were higher than those of [18F]MC225. Significant regional differences between tracers were found at baseline, which disappeared after inhibition. The positive slope of the SUV-TAC was positively correlated to the K1 and VT of both tracers. Conclusion [18F]MC225 and (R)-[11C]verapamil show comparable sensitivity to measure the P-gp function in non-human primates. Moreover, this study highlights the 30-min VT as the best parameter to measure decreases in the P-gp function with both tracers. [18F]MC225 may become the first radiofluorinated tracer able to measure decreases and increases in the P-gp function due to its higher baseline VT.

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(R)-[11C]Emopamil as a novel tracer for imaging enhanced P-glycoprotein function

Cited by 4 publications

References 31 publications

Use of PET Imaging to Evaluate Transporter‐Mediated Drug‐Drug Interactions

Use of PET Imaging to Evaluate Transporter‐Mediated Drug‐Drug Interactions

Head-to-head comparison of (R)-[11C]verapamil and [18F]MC225 in non-human primates, tracers for measuring P-glycoprotein function

Head to head comparison of (R)-[11C]verapamil and [18F]MC225 in non-human primates, tracers for measuring P-glycoprotein function

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