Development of probes for radiotheranostics with albumin binding moiety to increase the therapeutic effects of astatine-211 (At).

Purpose: We have developed probes for multiradionuclides radiotheranostics using RGD peptide ([Ga]Ga-DOTA-c[RGDf(4-I)K] ([Ga]1) and Ga-DOTA-[At]c[RGDf(4-At)K] ([At]2)) for clinical applications. The introduction of an albumin binding moiety (ABM), such as 4-(4-iodophenyl)-butyric acid (IPBA), that has high affinity with the blood albumin and prolongs the circulation half-life can improve the pharmacokinetics of drugs. To perform more effective targeted alpha therapy (TAT), we designed and synthesized Ga-DOTA-K([At]APBA)-c(RGDfK) ([At]5) with 4-(4-astatophenyl)-butyric acid (APBA), which has an astato group instead of an iodo group in IPBA. We evaluated whether APBA functions as ABM and [At]5 is effective for TAT. In addition, we prepared Ga-labeled RGD peptide without ABM, [Ga]Ga-DOTA-K-c(RGDfK) ([Ga]3), and I-labeled RGD peptide with ABM, Ga-DOTA-K([I]IPBA)-c(RGDfK) ([I]4), to compare with [At]5.

Methods: Biodistribution experiments of [Ga]3 without ABM, [I]4 and [At]5 with ABM were conducted in normal mice and U-87 MG tumor-bearing mice. In addition, two doses of [At]5 (370 or 925 kBq) were administered to U-87 MG tumor-bearing mice to confirm the therapeutic effects.

Results: The blood retention of [I]4 and [At]5 was remarkably increased compared to [Ga]3. Also, [I]4 and [At]5 showed similar biodistribution and significantly greater tumor accumulation and retention compared to [Ga]3. In addition, [At]5 inhibited tumor growth in a dose-dependent manner.

Conclusion: The functionality of APBA as ABM like IPBA, and the usefulness of [At]5 as the radionuclide therapy agent for TAT was revealed.