Distribution and pharmacokinetic analysis of angiostatin radioiodine labeled with high stability

Objective: Radiotracers of anticancer agents provide important information on its in vivo handling. Angiostatin (AST) is a promising anticancer drug with potent antiangiogenic effects, but reported AST radiotracers suffer from poor in vivo stability. In this study, we synthesized an AST probe radioiodinated via the Bolton-Hunter reagent (¹²⁵I-BH-AST) and investigated its stability and biokinetics in mice. Methods: ¹²⁵I-BH-AST and conventional direct radioiodinated ¹²⁵I-AST were evaluated for human endothelial cell binding characteristics. In vivo stability of the radiotracers was compared by biodistribution studies in normal ICR mice. Angiostatin pharmacokinetics was analyzed by serial blood sampling after intravenous injection of ¹²⁵I-BH-AST with varying AST concentrations in mice. Results: Both ¹²⁵I-AST and ¹²⁵I-BH-AST retained selective endothelial binding as demonstrated by dose-dependent inhibition by nonradiolabeled AST. ¹²⁵I-BH-AST was substantially more stable in mice than ¹²⁵I-AST, with 28- and 7-fold lower 24-h thyroid and blood activities, respectively (15.5±1.5 vs. 430.9±32.2 and 0.1±0.0 vs. 0.8±0.0 %ID/g; both P<.005). Using ¹²⁵I-BH-AST, we found that 24-h AST accumulation was highest in the kidneys, followed by the liver and lungs. Kinetic analysis of ¹²⁵I-BH-AST revealed AST to have linear pharmacokinetics with a T_1/2 of 5.8±2.6 h, volume of distribution (V_d) of 6.8±1.3 ml and clearance of 0.8±0.1 ml/h. Conclusion: Radioiodine-labeled AST prepared by the BH method provides a radioprobe with superior stability and improved in vivo biokinetics that is useful for distribution and pharmacokinetic studies.