Delving into the Latest Updates on [211At]YF-2 with Synapse

Overview

Basic Info

Drug Type

Therapeutic radiopharmaceuticals

Synonyms-

Target

PSMA

Action

inhibitors

Mechanism

PSMA inhibitors(Prostate-specific membrane antigen inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

Duke University

Active Organization

Duke University

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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.

01 Jul 2024·NUCLEAR MEDICINE AND BIOLOGY

A third generation PSMA-targeted agent [211At]YF2: Synthesis and in vivo evaluation

Article

Author: Vaidyanathan, Ganesan ; Finch, Sean W ; Zalutsky, Michael R ; Minn, Il ; Zheng, Yongxiang ; Feng, Yutian ; Meshaw, Rebecca L ; Pomper, Martin G

INTRODUCTION:

Targeted α-particle therapy agents have shown promising responses in patients who have developed resistance to β^--particle emitting radionuclides, albeit off-target toxicity remains a concern. Astatine-211 emits only one α-particle per decay and may alleviate the toxicity from α-emitting daughter radionuclides. Previously, we developed the low-molecular-weight PSMA-targeted agent [²¹¹At]L3-Lu that showed suitable therapeutic efficacy and was well tolerated in mice. Although [²¹¹At]L3-Lu had good characteristics, we now have evaluated a closely related analogue, [²¹¹At]YF2, to determine the better molecule for clinical translation.

METHODS:

The tin precursors and unlabeled iodo standards for [²¹¹At]YF2 and [²¹¹At]L3-Lu each were synthesized and a new one-step labeling method was developed to produce [²¹¹At]YF2 and [²¹¹At]L3-Lu from the respective tin precursor. RCY and RCP were determined using RP-HPLC. Cell uptake, internalization and in vitro cell-killing (MTT) assays were performed on PSMA⁺ PC-3 PIP cells in parallel experiments to compare [²¹¹At]YF2 and [²¹¹At]L3-Lu directly. A paired-label biodistribution study was performed in athymic mice with subcutaneous PSMA-positive PC-3 PIP xenografts as a head-to-head comparison of [¹³¹I]YF2 and [¹²⁵I]L3-Lu. The tissue distribution of [²¹¹At]YF2 and [²¹¹At]L3-Lu were determined individually in the same animal model.

RESULTS:

The syntheses of tin precursors and unlabeled iodo standards were accomplished in reasonable yields. A streamlined and scalable radiolabeling method (1 h total synthesis time) was developed for the radiosynthesis of both [²¹¹At]YF2 and [²¹¹At]L3-Lu with 86 ± 7 % (n = 10) and 87 ± 5 % (n = 7) RCY, respectively, and > 95 % RCP for both. The maximum activity of [²¹¹At]YF2 produced to date was 666 MBq. An alternative method that did not involve HPLC purification was developed that provided similar RCY and RCP. Significantly higher cell uptake, internalization and cytotoxicity was seen for [²¹¹At]YF2 compared with [²¹¹At]L3-Lu. Significantly higher uptake and longer retention in tumor was seen for [¹³¹I]YF2 than for co-administered [¹²⁵I]L3-Lu, while considerably higher renal uptake was seen for [¹³¹I]YF2. The biodistribution of [²¹¹At]YF2 was consistent with that of [¹³¹I]YF2.

CONCLUSION:

[²¹¹At]YF2 exhibited higher cellular uptake, internalization and cytotoxicity than [²¹¹At]L3-Lu on PSMA-positive PC3 PIP cells. Likewise, higher uptake and longer retention in tumor was seen for [²¹¹At]YF2. Experiments to evaluate the dosimetry and therapeutic efficacy of [²¹¹At]YF2 are under way.

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