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[11C]sorafenib: radiosynthesis and preliminary PET study of brain uptake in P-gp/Bcrp knockout mice
Chiharu Asakawa1, Masanao Ogawa, Katsushi Kumata
1Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
Abstract:
Sorafenib (Nexavar, BAY43-9006, 1) is a second-generation, orally active multikinase inhibitor that is approved for the treatment of some cancers in patients. In this Letter, we developed [(11)C]1 as a novel positron emission tomography (PET) probe, and evaluated the influence of ABC transporters-mediated efflux on brain uptake using PET with [(11)C]1 in P-glycoprotein (P-gp)/breast cancer resistance protein (Bcrp) knockout mice versus wild-type mice. [(11)C]1 was synthesized by the reaction of hydrochloride of aniline 2 with [(11)C]phosgene ([(11)C]COCl(2)) to give isocyanate [(11)C]6, followed by reaction with another aniline 3. Small-animal PET study with [(11)C]1 indicated that the radioactivity level (AUC(0-60 min), SUV×min) in the brains of P-gp/Bcrp knockout mice was about three times higher than in wild-type mice.
Insights
A novel PET probe, [(11)C]1, was developed to study cancer drug brain uptake. P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) significantly limit brain penetration of this sorafenib analog.
Area of Science:
- Radiochemistry
- Pharmacology
- Neuroscience
Background:
- Sorafenib is an orally active multikinase inhibitor used in cancer therapy.
- Understanding drug transport across the blood-brain barrier is crucial for developing effective brain-targeting cancer treatments.
Purpose of the Study:
- To develop a novel positron emission tomography (PET) probe, [(11)C]1, based on sorafenib.
- To investigate the role of P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) in limiting brain uptake of [(11)C]1 using PET imaging.
Main Methods:
- Synthesis of the novel PET tracer [(11)C]1.
- Small-animal PET imaging studies were conducted in wild-type mice and mice lacking P-gp and Bcrp (knockout mice).
- Quantification of brain radioactivity levels (Area Under the Curve and Standardized Uptake Value) over time.
Main Results:
- [(11)C]1 was successfully synthesized.
- Brain radioactivity levels in P-gp/Bcrp knockout mice were approximately three times higher than in wild-type mice.
- This indicates significant efflux of [(11)C]1 from the brain by P-gp and Bcrp.
Conclusions:
- The novel PET probe [(11)C]1 effectively visualizes the impact of ABC transporters on drug brain uptake.
- P-glycoprotein and breast cancer resistance protein play a critical role in limiting the brain penetration of sorafenib analogs.
- This finding has implications for designing brain-penetrant cancer therapeutics.
