Enhancing the therapeutic index of [211At]YF2 with iodo pseudo carrier: A simple strategy for reducing accumulation in kidneys, salivary and lacrimal glands.

INTRODUCTION: Low-molecular-weight (LMW) PSMA-targeted agents have enjoyed success; however, their off-target toxicity in normal tissues such as kidneys, salivary gland and lacrimal gland can be dose limiting. Herein, we have evaluated the effect of co-administration of the non-radioactive iodo pseudo carrier, iodo YF2, on the normal tissue uptake of [211At]YF2 in xenografted mice. The potential implications for clinical translation of these studies were investigated by evaluating the binding of LMW PSMA-targeted agents to murine and human PSMA. METHODS: [211At]YF2 was synthesized following established protocols. Groups of 5 mice bearing subcutaneous PSMA+ PC3 PIP xenografts received [211At]YF2 co-injected with varying i.v. doses of iodo YF2 (0-2 nmol), and the biodistribution was evaluated at 1 h post injection (p.i.). In another study, the biodistribution of [211At]YF2 alone and [211At]YF2 co-administered with 1.5 nmol iodo YF2 was evaluated at 1 and 8 h p.i. Bead-based radioligand binding assays were conducted for [131I]YF2 and several other LMW agents to compare their binding to human and murine PSMA. RESULTS: At 1 h, no significant difference was seen in kidney uptake of [211At]YF2 at iodo YF2 concentrations of 0, 0.05 and 0.1 nmol (p > 0.05), but renal accumulations significantly reduced by co-administering 2.0 nmol iodo YF2 (p < 0.0001). Decreases in salivary and lacrimal gland uptake also were observed at 1 h for [211At]YF2 co-injected with 0.1 nmol iodo YF2 (p < 0.05). A follow-up study revealed a kidney uptake of 1.8 ± 0.4 % ID/g for [211At]YF2 with 1.5 nmol iodo YF2, compared to 46.5 ± 7.7 % ID/g for [211At]YF2 alone at 8 h. Tumor uptake showed no significant difference (p > 0.05) between [211At]YF2 alone (17.1 ± 8.8 % ID/g at 1 h; 13.6 ± 5.3 % ID/g at 8 h) and [211At]YF2 plus 1.5 nmol iodo YF2 (12.8 ± 2.7 % ID/g at 1 h; 14.1 ± 3.2 % ID/g at 8 h). Bead-based radioligand binding assays showed that [131I]YF2 has the highest binding fractions to both human PSMA (94.1 ± 0.1 %) and murine PSMA (92.5 ± 0.2 %) with minimal differences between the two, while [177Lu]PSMA-617 had the greatest species-dependent disparity with a binding fraction of 90.5 ± 0.3 % to human PSMA and 60.9 ± 1.4 % to murine PSMA. CONCLUSIONS: Co-administration of iodo YF2 reduced kidney uptake of [211At]YF2 and decreased accumulation in normal tissues with no significant change in tumor uptake. In some cases, there was a significant difference in binding to human and murine PSMA among LMW PSMA-targeted agents suggesting that particularly for some agents, applying mouse data to predict human dosimetry must be done with caution.

Duke Scholars

Author Ganesan Vaidyanathan Radiology

Author Michael Rod Zalutsky Radiology