Versatile Bifunctional PYTA Derivatives for ²²⁵Ac Radiolabeling: A Comparison to Gold Standards

Area of Science:

• Radiochemistry
• Medicinal Chemistry
• Nuclear Medicine

Background:

• Actinium-225 (²²⁵Ac) is a promising alpha-emitter for targeted cancer therapy.
• Development of stable chelators for ²²⁵Ac is crucial for effective radiopharmaceutical applications.
• Existing chelators may have limitations in stability or synthesis.

Purpose of the Study:

• To synthesize and evaluate novel bifunctional chelators (BFCs) based on 3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane-3,6,10,13-tetraacetic acid (PYTA) for ²²⁵Ac coordination.
• To compare the performance of PYTA BFCs with established chelators like MACROPA and DOTA.
• To assess the in vitro and in vivo stability and applicability of PYTA-based radioconjugates.

Main Methods:

• Synthesis of three PYTA BFC derivatives: PYTA-triacetate, PYTA-glutaric acid, and PYTA-pyridyl-ether.
• Comparative radiolabeling studies with ²²⁵Ac using PYTA, MACROPA, DOTA, and crown derivatives.
• Conjugation of PYTA BFCs to prostate-specific membrane antigen ligands and antibodies.
• In vitro stability assays and in vivo biodistribution studies in animal models.

Main Results:

• PYTA derivatives exhibited excellent radiochemical properties, achieving quantitative radiolabeling under mild conditions (37°C, low concentration).
• PYTA-based radioconjugates demonstrated prolonged in vitro and in vivo stability, comparable to MACROPA.
• Crown derivatives showed instability in vivo, while PYTA conjugates maintained integrity.

Conclusions:

• PYTA bifunctional chelators represent a promising new class of chelators for ²²⁵Ac coordination.
• PYTA chelators offer comparable performance to MACROPA with the added advantage of modular synthesis.
• These findings support the potential of PYTA for developing advanced ²²⁵Ac-based radiopharmaceuticals.