Abstract | OBJECTIVE: METHODS: We synthesized [(11)C] XR9576 by methylation of 7-O-desmethyl XR9576 with [(11)C] methyl iodide. In in vivo tissue distribution, the effects of co-injection with XR9576 on the uptake of [(11)C] XR9576 in mice were investigated. PET studies using [(11)C] XR9576 were performed in P-gp and/or Bcrp knockout mice as well as in wild-type mice. Metabolites of [(11)C] XR9576 were measured in the brain and plasma of mice. RESULTS: [(11)C] XR9576 was successfully synthesized with suitable radioactivity for injection as well as appropriate radiochemical purity and stability. In in vivo tissue distribution, the brain uptake of [(11)C] XR9576 significantly increased about tenfold of control on co-injection with >10 mg/kg of XR9576. In PET studies, the AUC(brain) ([0-60 min]) in P-gp and P-gp/Bcrp knockout mice was 2- and 11-fold higher than that in wild-type mice. [(11)C] XR9576 showed a high metabolic stability (>90% unchanged form) in the brain and plasma of mice 30 min after injection. These results suggest that a tracer amount of [(11)C] XR9576 behave as the P-gp and Bcrp substrate, and the increased brain uptake or AUC(brain) of [(11)C] XR9576 correlates with P-gp and Bcrp functions. CONCLUSIONS: PET studies using [(11)C] XR9576 may be a promising approach for evaluating deficiency of the function of drug efflux transporters targeting intracranial diseases and tumors.
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Authors | Kazunori Kawamura, Fujiko Konno, Joji Yui, Tomoteru Yamasaki, Akiko Hatori, Kazuhiko Yanamoto, Hidekatsu Wakizaka, Makoto Takei, Nobuki Nengaki, Toshimitsu Fukumura, Ming-Rong Zhang |
Journal | Annals of nuclear medicine
(Ann Nucl Med)
Vol. 24
Issue 5
Pg. 403-12
(Jun 2010)
ISSN: 1864-6433 [Electronic] Japan |
PMID | 20361276
(Publication Type: Journal Article)
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Chemical References |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Carbon Radioisotopes
- Quinolines
- tariquidar
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Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(metabolism)
- Animals
- Biological Transport
(drug effects)
- Brain
(drug effects, metabolism)
- Carbon Radioisotopes
- Injections
- Male
- Mice
- Positron-Emission Tomography
(methods)
- Quinolines
(blood, chemical synthesis, metabolism)
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