177Lu-M3-12: a Novel PSMA-Targeted Radioligand Shows Higher Tumour Uptake Than 177Lu-PSMA-617 in Preclinical Study

A new preclinical study published in EJNMMI Research reports promising results for 177Lu-M3-12, an experimental PSMA-targeted radioligand designed to improve tumour targeting and potentially reduce radiation exposure to healthy tissues in prostate cancer.

The treatment uses lutetium-177, the same radioactive isotope employed in 177Lu-PSMA-617 (Pluvicto), but incorporates a different molecular structure featuring a hydrophilic linker. The researchers investigated whether this modification could improve PSMA binding, tumour accumulation and the distribution of radioactivity between malignant tissue and healthy organs.

Laboratory experiments demonstrated stronger PSMA binding for M3-12 than for PSMA-617.The researchers subsequently compared the two radioligands in mice bearing PSMA-positive LNCaP prostate cancer tumours.

At 24 hours after administration, ¹⁷⁷Lu-M3-12 achieved tumour uptake of 44.69% of the injected dose per gram of tissue, compared with 24.09% for ¹⁷⁷Lu-PSMA-617. This represented approximately 1.85 times greater tumour accumulation. The tumour-to-kidney uptake ratio was also 2.73 times higher, suggesting potentially more favourable distribution of radioactivity.

Treatment experiments demonstrated dose-dependent antitumour activity, with pronounced effects at the highest tested activity of 29.6 MBq and no significant toxicity reported under the experimental conditions. These findings suggest that molecular modifications to existing PSMA-targeting compounds could improve tumour delivery while potentially limiting exposure to organs such as the kidneys.

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