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Substrates, Inhibitors and Activators of P-glycoprotein: Candidates for Radiolabeling and Imaging Perspectives

[ Vol. 10 , Issue. 17 ]


Nicola A. Colabufo, Francesco Berardi, Maria Grazia Perrone, Elena Capparelli, Mariangela Cantore, Carmela Inglese and Roberto Perrone   Pages 1703 - 1714 ( 12 )


In recent years, several PET tracers for monitoring the activity and expression of P-gp at the BBB have been tested. P-gp substrates such as [11C]verapamil and [11C]loperamide can be employed to visualize P-gp activity, but they display a moderate baseline uptake in the brain and formation of radiolabeled metabolites which hamper the interpretation of PET data. P-gp inhibitors such as [11C]elacridar, [11C]laniquidar and [11C]tariquidar have been tested to investigate Pgp expression and the results need further investigation. Recently, we developed MC18, MC266 and MC80, that have been characterized as an inhibitor, substrate and inducer of P-gp both by in vitro assays and in the everted gut sac method. These compounds have been radiolabelled with 11C and been evaluated in vivo. In the present review, we compare the outcome of biological in vitro assays and the corresponding in vivo PET data for the P-gp inhibitors [11C]MC18 and [11C]elacridar, the P-gp substrates [11C]MC266 and [11C]verapamil, the P-gp inducer [11C]MC80 and the P-gp modulator cyclosporin A. Since a satisfactory overlap was found comparing in vivo results and the corresponding in vitro findings, the proposed biological in vitro assays could be predictive for the in vivo PET data of novel radiotracers. PET tracers could be employed for various purposes: radiolabeled P-gp inhibitors to monitor decreased expression of P-gp at the BBB in neurodegenerative disorders such as Alzheimers and Parkinsons disease; and radiolabeled P-gp substrates with a high baseline uptake to monitor increased expression of P-gp in epileptic foci.


ATPase, PET studies, Caco-2, Rhodamine-123, MCF7/adr cell line, Doxorubicin, Acetoxymethyl ester, Madin-Darby Canine Kidney cells, P-gp expression, [11C]MC80, [11C]MC266, [11C]MC18, Cyclosporin A, Pgp modulators, CYP3A4, P-gp inhibitor, P-gp knock-out mice, Radiometabolites, C]N-desmethyl-loperamide, Radiotracer, P-gp substrates, CYP450, (R)- and (S)-enantiomers, Tariquida, Laniquidar, Elacridar, [99mTc]complexes, [68Ga]complexes, [64Cu]complexes, [11C]loperamide, [11C]verapamil, Multi Drug Resistance (MDR), ATP-Binding Cassette (ABC) transporter family, expression, function, inducer, modulator, substrate, inhibitor, PET, P-glycoprotein


Dipartimento Farmacochimico,Universita degli Studi di Bari, “A. Moro”, via Orabona 4,70125 Bari, Italy.

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