Evaluation of lysine-urea-glutamate derivatives that contain closo-decaborate(2-) moieties for targeting astatine-211 to metastatic prostate cancer

1048 Objectives The objective was to prepare 3 compounds of varying MW, containing lysine-urea-glutamate and closo-decaborate(2-) moieties, for evaluation of targeting to C4-2B prostate cancer xenografts in SCID mice. Methods Compound 1a (1602Da), containing a lysine-urea-glutamate (lys-U-glu) moiety with dPEG linker, a closo-decaborate(2-) (B10) moiety with dPEG linker and a N-acetyl-lysine moiety, was synthesized. Compound 2a (1301Da), having the same structure as 1a without lys-U-glu, was synthesized as a control. Compounds 3a (4756Da) & 4a (9911Da), containing 4 or 8 lys-U-glu and B10 moieties, was synthesized using either PAMAM gen. 0 or gen. 1 as core structures. The lys-U-glu-containing compounds and the control compound were labeled with 125I or 131I so dual-label biodistribution studies could be conducted. Admixtures of [131I]1b/[125I]2b or [125I]3b/[131I]4b were injected into SCID mice bearing C4-2B xenografts, and biodistributions were determined at 1 & 4 h post injection. Results The targeted compounds (1a,2a,3a,4a) were prepared in multi-step syntheses. Each compound was radiolabeled with 125I or 131I. [131I]1b & [125I]2b were isolated in 89% & 68% rcy. [125I]3b & [131I]4b were isolated in 62% & 50% rcy. [131I]1b demonstrated targeting of C4-2B xenografts (~4.3±0.26%ID/g@1h), but the control [125I]2b did not target tumor (0.43±0.27%ID/g@1h). Interestingly, [125I]2b, which did not contain lys-U-glu, had low concentrations in kidney (1.68±2.39%ID/g@1h), whereas [131I]1b had high kidney concentrations (74.47±18.39%ID/g@1h). Compounds [125I]3b and [131I]4b had slightly increased tumor targeting (4-6%ID/g) compared with [131I]1b, but had decreased kidney concentrations (42%) and increased liver (2-4%ID/g vs. 0.6%ID/g) concentrations at 4h. Conclusions The compounds tested had good tumor targeting but kidney concentrations were too high for 211At use. Studies are planned to determine if cleavable linkers bonded to B10 will decrease kidney concentrations. Research Support We thank the National Institutes of Health (CA113431) for funding this research.