NDLI: Lysosomal trapping of a radiolabeled substrate of P-glycoprotein as a mechanism for signal amplification in PET

Content Provider	PubMed Central
Author	Kannan, Pavitra Brimacombe, Kyle R. Kreisl, William C. Liow, Jeih-san Zoghbi, Sami S. Sanjay, Telu Zhang, Yi Pike, Victor W. Halldin, Christer Gottesman, Michael M. Innis, Robert B. Hall, Matthew D.
Abstract	The radiotracer [11C]N-desmethyl-loperamide (dLop) images the in vivo function of P-glycoprotein (P-gp), a transporter that blocks the entry of drugs that are substrates into brain. When P-gp is inhibited, [11C]dLop, a potent opiate agonist, enters and becomes trapped in the brain. This trapping is beneficial from an imaging perspective, because it amplifies the PET signal, essentially by accumulating radioactivity over time. As we previously demonstrated that this trapping was not caused by binding to opiate receptors, we examined whether [11C]dLop, a weak base, is ionically trapped in acidic lysosomes. To test this hypothesis, we measured [3H]dLop accumulation in human cells by using lysosomotropics. Because the in vivo trapping of dLop was seen after P-gp inhibition, we also measured [3H]dLop uptake in P-gp–expressing cells treated with the P-gp inhibitor tariquidar. All lysosomotropics decreased [3H]dLop accumulation by at least 50%. In P-gp–expressing cells, tariquidar (and another P-gp inhibitor) surprisingly decreased [3H]dLop uptake. Consequently, we measured [11C]dLop uptake before and after tariquidar preadministration in lysosome-rich organs of P-gp KO mice and humans. After tariquidar pretreatment in both species, radioactivity uptake in these organs decreased by 35% to 40%. Our results indicate that dLop is trapped in lysosomes and that tariquidar competes with dLop for lysosomal accumulation in vitro and in vivo. Although tariquidar and dLop compete for lysosomal trapping in the periphery, such competition does not occur in brain because tariquidar has negligible entry into brain. In summary, tariquidar and [11C]dLop can be used in combination to selectively measure the function of P-gp at the blood–brain barrier.
Related Links	http://dx.doi.org/10.1073/pnas.1014641108
Ending Page	2598
Page Count	6
Starting Page	2593
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	6
Volume Number	108
Language	English
Publisher	National Academy of Sciences
Publisher Date	2011-02-08
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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