Radiopharmacological investigation of 3-[4’-[F]fluorobenzylidenyl]-indolin-2-one

Introduction and Aim:

The radiopharmacological evaluation of the new compound 3-[4’-[18F]fluorobenzylidenyl]-indolin-2-one is described. The compound is a radiolabeled derivative of an inhibitor of the VEGF-mediated signaling through the Flk-1/KDR (VEGFR-2) tyrosine kinase receptor pathway (SU5416 (NSC 696819) [3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one]).

Materials and Methods:

The radiosynthesis was accomplished by Knoevenagel condensation of 4-[18F]fluorobenzaldehyde with oxindole in a remotely controlled synthesis module. The radiotracer was obtained after a two-step labeling procedure in 4% decay-corrected radiochemical yield at a specific activity of 48-61 GBq/µmol within 90 min. The radiochemical purity after semi-preparative HPLC purification exceeded 98%. The biodistribution, metabolism and excretion were studied in Wistar rats. Small animal PET studies in rats and FaDu tumor bearing nude mice were carried out. Results: After distribution the radiotracer was rapidly accumulated in the adrenals, liver and kidneys, however, it was cleared from these and the most other organs. Only the adipose tissue retained the activity over 60 min. Unexpected high transient uptake was observed in the brain, pancreas, heart and lung. The fast blood clearance of 3-[4’-[18F]fluorobenzylidenyl]-indolin-2-one was caused by excretion, approximately one half each was renal and biliary excreted and other metabolic processes. Only the original compound was entering the brain. In arterial blood plasma were two more polar radiometabolites detected. The blood clearance was fast and could be described by a two phase elimination with half-lifes of 8 and 267 s. Consequently, in small animal PET studies with FaDu tumor bearing mice - no specific uptake in the tumors could be detected.

Conclusion:

The investigation of the 3-[4’-[18F]fluorobenzylidenyl]-indolin-2-one revealed that the uptake in high perfused organs was transiently, and only in the adipose tissue the compound was accumulated. However, it seems to be it is not applicable for angiogenesis imaging.