211At-Labeled Small-Molecule PSMA Inhibitors: Effect of Structure on Biodistribution in Mice

Objectives Radiolabeled small-molecule PSMA inhibitors are currently under clinical investigation as imaging and radiotherapeutic agents for prostate cancer (PC). Astatine-211 is a 7.2-h radiohalogen emitting short range, high linear energy transfer alpha particles well suited for treatment of PC micrometastases. Such an application requires an optimized biodistribution where the agent rapidly clears from non-target organs including kidneys. Here we report the preparation and biodistribution of five 211At-labeled agents.

Methods Compounds 1-5 were labeled with 131I or 211At by the reaction of the respective stannylated precursor (triester) with 131I- or 211At in methanol containing N-chlorosuccinimide and acetic acid followed by concentration, acid hydrolysis and purification by high-performance liquid chromatography. PSMA inhibitory activity was measured by the Amplex Red glutamic acid assay. Biodistribution was performed using an IV bolus of 185 kBq (5 µCi) into mice bearing both PSMA+ PC3-PIP and PSMA- PC3-flu flank xenografts. Organs were harvested at 1, 2, 4, and 21 h post injection (n = 5 per time point).

Results All agents were potent inhibitors [Ki = 1, (0.01), 2 (0.3), 3 (6.8), 4 (1.8), 5 (0.01) nM]. [211At]1-4 exhibited high kidney uptake at 1 h (99 ± 27 %ID/g) that cleared to 5.8 ± 6.9 %ID/g at 21 h except for [211At]1 (57 ± 7.4 %ID/g). [211At]5 had a lower 1 h kidney uptake (46.7 ± 8.2 %ID/g), which cleared (2.6% ± 0.8 %ID/g at 21 h, post-injection). [211At]5 also had a higher tumor uptake at 1 h (43.2 ± 9.8 %ID/g) compared to [211At]1-4 (17.8 ± 4.6 %ID/g). By 21 h tumor decreased to 12.2 ±5.3 %ID/g for [211At]2-5 but [211At]1 increased to 31.1 ± 9.8 %ID/g. [211At]1, 4, and 5 had significant stomach accumulation at 21 h (9.4-12.6 %ID/g) indicating possible de-astatination. Thyroid uptake at 21 h was 6.5 ± 2.0, 2.2 ± 1.0, 0.9 ± 0.1, 3.7 ± 1.4, and 3.8 ± 0.6 %ID/organ for [211At]1-5, respectively. Compared to [211At]5, [131I]5 had a higher 1 h kidney and tumor uptake (106 ± 19 and 78 ± 19 %ID/g) that cleared to 3.1 ± 1.6 and 23 ± 22 %ID/g at 21 h but lower stomach and thyroid uptake (0.10 ± 0.04 %ID/g and 0.40 ± 0.05 %ID/organ at 21 h).

Conclusions Although exhibiting possible deastatination in vivo, [211At]5, with its high initial tumor uptake and lowest kidney uptake, is a promising agent for further study.

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