Synthesis and radiolabelling of PSMA-targeted derivatives containing GYK/MVK cleavable linkers

Area of Science:

• Oncology
• Radiochemistry
• Medicinal Chemistry

Background:

• Targeted radionuclide therapy (TRT) offers a promising approach for cancer treatment by delivering therapeutic radionuclides to tumor sites.
• Prostate-specific membrane antigen (PSMA) is a key target for prostate cancer therapies, with low molecular weight ligands being actively developed.
• Optimizing the pharmacokinetic properties of PSMA-targeting ligands is crucial for enhancing therapeutic efficacy and minimizing off-target toxicity, particularly to the kidneys.

Purpose of the Study:

• To synthesize and evaluate novel PSMA-targeting conjugates with cleavable linkers (Gly-Tyr-Lys and Met-Val-Lys) designed to reduce radiation dose to the kidneys.
• To assess the radiolabeling efficiency and stability of these new conjugates using therapeutic and imaging radionuclides (In-111 and Lu-177).

Main Methods:

• Solid-phase peptide synthesis (SPPS) was employed to create the new conjugates with high chemical purity (>95%).
• Radiolabeling was performed with Indium-111 (In-111) and Lutetium-177 (Lu-177) to evaluate imaging and therapeutic potential.
• Radiochemical purity and stability, including assessment of radiolysis, were determined for the radiolabeled compounds.

Main Results:

• The synthesized conjugates achieved high chemical purity (>95%) and radiochemical purity (>80%) for both In-111 and Lu-177.
• The Gly-Tyr-Lys (GYK) conjugate demonstrated promising characteristics, while the methionine-containing analogue (MVK) exhibited significant radiolysis, indicating potential instability.
• The GYK-PSMA conjugate showed potential for further biological evaluation as a TRT agent.

Conclusions:

• The novel GYK-PSMA conjugate represents a potential advancement in targeted radionuclide therapy for prostate cancer by aiming to reduce renal toxicity.
• The findings suggest that cleavable linkers can be effectively incorporated into PSMA-targeting agents to modulate pharmacokinetic profiles.
• Further preclinical studies are justified to fully explore the therapeutic and imaging capabilities of the GYK-PSMA conjugate.