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Effect of a P‐glycoprotein inhibitor, cyclosporin A, on the disposition in rodent brain and blood of the 5‐HT 1A receptor radioligand, [ 11 C]( R )‐(––)‐RWAY
Author(s) -
Liow JeihSan,
Lu Shuiyu,
McCarron Julie A.,
Hong Jinsoo,
Musachio John L.,
Pike Victor W.,
Innis Robert B.,
Zoghbi Sami S.
Publication year - 2007
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20348
Subject(s) - radioligand , ex vivo , chemistry , in vivo , knockout mouse , blood–brain barrier , pharmacology , receptor , p glycoprotein , endocrinology , medicine , in vitro , biology , biochemistry , central nervous system , microbiology and biotechnology , antibiotics , multiple drug resistance
Limited brain uptake of radioligands with otherwise optimal properties for imaging brain receptors can be improved by blocking the effect of P‐glycoprotein (P‐gp), an efflux pump at the blood‐brain barrier. Using small animal positron emission tomography (PET), we investigated how P‐gp and its blockade with Cyclosporin A (CsA) affect rodent brain uptake of [ 11 C]( R )‐(−)‐RWAY, a radioligand for brain 5‐HT 1A receptors. Brain uptake of radioactivity was compared in control and CsA‐treated rats as well as P‐gp knockout and wild type mice. Parent radioligand and radiometabolite in plasma and brain samples were determined at 30 min after injection of radioligand. PET binding potential ( BP ) was calculated with a reference tissue model. P‐gp knockout mice had 2.5‐ and 2.8‐fold greater brain uptake of [ 11 C]( R )‐(−)‐RWAY than wild type ones, measured by in vivo PET and ex vivo tissue sampling, respectively. Similarly, CsA increased rat brain uptake 4.9‐ and 5.3‐fold, in vivo and ex vivo. In addition, CsA increased the plasma free fraction of [ 11 C]( R )‐(−)‐RWAY in rats by 2.7‐fold. Although CsA increased brain uptake in wild type mice by 2.5‐fold, it had no effect on plasma free fraction in knockout animals. Three radiometabolites of [ 11 C]( R )‐(−)‐RWAY were uniformly distributed in rat brain, suggesting they were inactive. CsA treatment increased brain uptake of [ 11 C]( R )‐(−)‐RWAY and only one of its radiometabolites. Regional rat brain BP increased 27–70% in the CsA‐treated rats and the P‐gp knockout mice. [ 11 C]( R )‐(−)‐RWAY is a P‐gp substrate in rat and mouse. The effects of CsA in rats are mediated by both P‐gp blockade and displacement of the radiotracer from plasma proteins. Studies with wild type and knockout mice showed that CsA affected only P‐gp in this species. Synapse 61:96–105, 2007. © 2006 Wiley‐Liss, Inc.