Radiosynthesis of 5-(2-[¹⁸F]fluoroethyl)-sunitinib, an inhibitor of VEGFR-2

Ziel/Aim:

Sunitinib is a multi-tyrosine kinase inhibitor (TKI) targeting VEGFR, PDGFR and FLT-3. Radiolabeled sunitinib might be suitable probe for monitoring angiogenesis with PET and to facilitate the success of corresponding anti-angiogenic
chemotherapy for the individual patient. For this purpose we developed an fluorine-18 radiolabeled PET tracer, 5-(2-[¹⁸F]fluoroethyl)-sunitinib basing on the lead structure of sunitinib.
Methodik/Methods:
The reference compound 5-(2-fluoroethyl)-sunitinib was synthesized by Knoevenagel condensation of 5-(2-fluoroethyl)-indoline-2-one with N-[2-(diethylamino)ethyl]-2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxamide. Two suitable precursors for radiolabeling were obtained by reacting 5-(2-bromoethyl)-substituted sunitinib with AgC7H7SO3 and AgCH3SO3, respectively. In a set of experiments for finding the optimal radiolabeling conditions 4 mg of each
precursor was reacted with [¹⁸F]fluoride at a scheduled temperature regime for 20 min in acetonitrile, DMF or DMSO.
Ergebnisse/Results:
In a competition binding assay against VEGFR-2 a Kd value of 9 nM for 5-(2-fluoroethyl)-sunitinib was determined. For radiolabeling with [¹⁸F]fluoride the methanesulfonyl-substituted precursor in acetonitrile gave radiochemical yields up to 8%. In large scale synthesis using a TracerLAB (GE) synthesiser 8mg of precursor were reacted with 10 GBq of [¹⁸F]fluoride in acetonitrile at 110°C for 12 min. After semi-preparative HPLC purification and SPE separation 115-135 MBq of 5-(2-[¹⁸F]fluoroethyl)-sunitinib could be obtained in radiochemical purity > 95% and in a specific activity of 38-62 GBq/[mu]mol.
Schlussfolgerungen/Conclusions:
The new VEGFR-2 targeted radiolabeled probe 5-(2-[¹⁸F]fluoroethyl)-sunitinib was successfully synthesized by radiofluorination of the corresponding methanesulfonyl-substituted precursor with [¹⁸F]fluoride. The radiotracer can be obtained in high chemical and radiochemical purity in 100 MBq scale.