Radiosynthesis of ₁₈F-cabozantinib, a small molecule angiokinase inhibitor

Ziel/Aim:

Cabozantinib is a highly affine receptor tyrosine kinase (angiokinase) inhibitor (TKI) selectively targeting VEGFR-2 and c-Met. Radiolabeled cabozantinib might be a valuable probe to monitor induction of angiogenesis and the success of anti-angiogenic therapy in vivo. For this purpose, we developed ¹⁸F-cabozantinib, a potential PET tracer where the already existing fluorine atom is replaced by fluorine-18.
Methodik/Methods:
The radiotracer ¹⁸F-cabozantinib is obtained via a condensation of an acyl chloride precursor with 4-[¹⁸F]fluoroaniline. Briefly, 1,4-dinitrobenzene reacts with [¹⁸F]fluoride in DMSO for 5 min at 140°C to build 4-[¹⁸F]fluoronitrobenzene which subsequently is separated by SPE and eluted with methanol. Reduction with Pd/C and NaBH₄ then delivered 4-[¹⁸F]fluoroaniline which is trapped on a second SPE cartridge and eluted with THF to the precursor to form ¹⁸F-cabozantinib.
Ergebnisse/Results:
1-[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylcarbamoyl]-cyclopropanecarbonyl chloride as precursor was synthesized via three steps in 48% overall yield. 4-[¹⁸F]fluoroaniline was obtained in > 50 radiochemical yield (dc) after cartridge purification. By large scale synthesis via a TracerLAB (GE) synthesizer comprising ¹⁸F-fluorination and reduction, 4-[¹⁸F]fluoroaniline was produced in a 2 GBq scale. 10 mg of the acyl chloride precursor was reacted with 2 GBq of 4-[¹⁸F]fluoroaniline in THF at ambient temperature for 15 min to build ¹⁸F-cabozantinib with > 90% radiochemical yield. Final semi-preparative HPLC purification delivered ¹⁸F-cabozantinib in radiochemical purity > 95% and a specific activity > 20 GBq/µmol.
Schlussfolgerungen/Conclusions:
In a multitude of experiments the optimal conditions for radiosynthesis and purification of -[¹⁸F]fluoroaniline and ¹⁸F-cabozantinib could be established. By a partly automated procedure the small molecule angiokinase inhibitor ¹⁸F-cabozantinib was successfully synthesized in high chemical and radiochemical purity in a 200 MBq scale.