Synthesis and Preclinical Evaluation of Novel PET Probes for P-Glycoprotein Function and Expression

Aren van Waarde*, Nisha K. Ramakrishnan, Anna A. Rybczynska, Philip H. Elsinga, Francesco Berardi, Johan R. de Jong, Chantal Kwizera, Roberto Perrone, Mariangela Cantore, Jurgen W. A. Sijbesma, Rudi A. Dierckx, Nicola A. Colabufo

*Corresponding author for this work

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P-glycoprotein (P-gp) is an ATP-dependent efflux pump protecting the body against xenobiotics. A P-gp substrate (7) and an inhibitor (6) were labeled with (11)C, resulting in potential tracers of P-gp function and expression. Methods: 6 and 7 were labeled using (11)CH(3)I. (11)C-verapamil was prepared as published previously, using (11)C-methyl triflate. MicroPET scans (with arterial sampling) and biodistribution studies were performed in rats pretreated with saline, cyclosporin A (CsA, 50 mg/kg), or cold 6 (15 mg/kg). Results: The radiochemical yields of (11)C-6 and (11)C-7 were approximately 30% with a total synthesis time of 45 min. Cerebral distribution volumes (DV) of (11)C-6 (2,35 +/- 0.11) and (11)C-7 (1.86 +/- 0.15) in saline-treated rats were higher than or (11)C-verapamil (0.64 +/- 0.12). DVs of (11)C-7 and (11)C-verapamil were significantly increased by CsA (to 5.26 +/- 0.14 and 5.85 +/- 0.32, respectively). The DV of (11)C-6 was reduced by cold 6 (to 1.65 +/- 0.03). Its uptake was also reduced (up to 67%) in several peripheral organs that express P-gp. Conclusions: (11)C-7 is a novel tracer of P-gp function with higher baseline uptake than (11)C-verapamil. Upregulation of P-gp function in response to treatment (which is hard to detect with (11)C-verapamil) may be detectable using (11)C-7 and PET. Because (11)C-6 shows specific binding in target organs, this compound is the First PET tracer allowing measurement of P-gp expression.

Original languageEnglish
Pages (from-to)4524-4532
Number of pages9
JournalJournal of Medicinal Chemistry
Issue number14
Publication statusPublished - 23-Jul-2009


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