Synthesis and first radiopharmaceutical investigation of 5-[125I]Iodo-SU11248, a potential radiotracer for imaging VEGFR

Aim: Due to the fact that receptor tyrosine kinases (RTKs) are overexpressed in some tumour entities, they might be a suitable target for PET or SPECT imaging. Then, tyrosine kinase inhibitors labeled with a radioisotope could represent a useful tool for monitoring levels of RTKs in tumour tissue giving valuable information for anti‐angiogenic therapy. SU11248 (Sunitinib®) is a novel highly potent RTK inhibitor targeting vascular endothelial growth factor receptor (VEGFR)
(IC50=0.08μM) [1]. We report here the synthesis of a 125I‐labeled derivative of SU11248 and its first radiopharmaceutical characterization.
Materials and methods: 5‐[125I]lodo‐SU11248 was obtained via destannylation of the corresponding tributylstannyl precursor with [125I]NaI in the presence of H2O2. The radioiodinated compound has been purified by RP‐HPLC with UV and radioactivity detection using methanol/0.1% TFA (85:15) as eluent. Determination of human plasma protein binding at time intervals of 0; 1; 2; 4 and 24h was accomplished by incubation of the radiotracer in fresh human serum at 37°C. Preliminary biodistribution studies were carried out in healthy CD‐1 mice and in vivo stability was assessed by HPLC analysis of urine samples collected at sacrifice time.
Results: 5‐[125I]Iodo‐SU11248 could be obtained in high radiochemical yield (>95%). After HPLC purification the radiochemical purity exceeded 98%. The identity of the radiotracer was confirmed by co‐elution with 5‐Iodo‐SU11248 as reference compound [2]. Lipophilicity of 5‐[125I]Iodo‐SU11248 has been assessed using the octanol/PBS partition coefficients (logPo/w) and was found to be 2.25. Determination of human plasma protein binding suggested a low non‐specific binding of 5‐10%. Biodistribution studies showed a relatively high uptake in VEGFR‐2 rich tissues like kidney and lung, followed by rapid washout (9.6 and 9.7; 4.5 and 3.8% ID/g kidney and lung at 1 and 4 h, respectively).
Conclusion: The new 5‐[125I]Iodo‐SU11248 was synthesized in high radiochemical yield and purity. The high stability in human serum and urine samples, suggests that the tracer is not significantly metabolized. The ability of 5‐Iodo‐SU11248 to inhibit tyrosine kinase activity, a mandatory prerequisite for further studies on RTK expressing cells, is underway, to disclose whether this radiotracer would be a useful tool for monitoring VEGFR expression. Ultimately, the radiochemical profile of 5‐[125I]Iodo‐SU11248 associated to a low non‐specific binding and rapid clearance from most tissues encourages further radiolabeling with other radioisotopes, such as 123I for SPECT or 124I for PET.
[1] Sun L., Liang C. et al., J. Med. Chem., 46, (2003), 1116 [2] Kniess T., Oliveira C. et al., unpublished results