Dansylated Amino Acid–Modified Long-Acting PSMA Derivatives⁶⁸Ga/¹⁷⁷Lu-LNC1011 as Prostate Cancer Theranostics

Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical therapy has demonstrated promising potential for treating metastatic castration-resistant prostate cancer. Recently, albumin-binding motif-modified PSMA radioligands with prolonged blood circulation were developed to improve tumor uptake and therapeutic effectiveness, properties which, however, were associated with an increased risk of bone marrow toxicity. This study presents new PSMA-targeted radioligands incorporating dansylated amino acids as relatively weak and preferable albumin binders to achieve a fine balance between increased tumor accumulation, safety, and diagnostic efficacy, facilitating a unified approach to theranostics within a single molecular framework. <b>Methods:</b> Three novel PSMA ligands ([⁶⁸Ga]Ga-Dan-Gly-PSMA, [⁶⁸Ga]Ga-Dan-Nva-PSMA, and [⁶⁸Ga]Ga-Dan-Phe-PSMA, denoted as [⁶⁸Ga]Ga-LNC1011) were synthesized with dansylated amino acids and measured the albumin-binding properties with human serum albumin through ultrafiltration experiments. Binding affinity and PSMA-targeting specificity were investigated using a saturation binding assay and cell uptake in the PSMA-induced prostate cancer 3 cell line (PC3-PIP). PET imaging in PC3-PIP tumor-bearing mice was performed to evaluate the preclinical pharmacokinetics and diagnostic efficiency of ⁶⁸Ga-labeled PSMA ligands. Tumor uptake of [¹⁷⁷Lu]Lu-LNC1011 was evaluated through SPECT/CT imaging and biodistribution studies. Radiopharmaceutical therapy studies were conducted to systematically assess the therapeutic effect of the radioligand. <b>Results:</b> Three novel PSMA radioligands ([⁶⁸Ga]Ga-Dan-Gly-PSMA, [⁶⁸Ga]Ga-Dan-Nva-PSMA, and [⁶⁸Ga]Ga-LNC1011) with various dansylated amino acids were successfully synthesized with a radiochemical yield greater than 97%. In the PC3-PIP xenograft tumor model, the tumor/heart, tumor/liver, tumor/kidney, and tumor/muscle ratios were 9.82 ± 2.35, 12.42 ± 3.71, 4.36 ± 0.29, and 52.88 ± 12.08 at 4 h after injection, respectively. Biodistribution studies confirmed the significantly higher tumor uptake of [¹⁷⁷Lu]Lu-LNC1011 (127.36 ± 16.95 %ID/g) over [¹⁷⁷Lu]Lu-PSMA-617 (17.44 ± 6.29 %ID/g) at 4 h after injection, and no decrease was measured for the [¹⁷⁷Lu]Lu-LNC1011 at up to 72 h after injection, which was corroborated with SPECT imaging. A single injection of 9.3 MBq of [¹⁷⁷Lu]Lu-LNC1011 achieved 89.43% inhibition of tumor growth, equivalent to 18.5 MBq of [¹⁷⁷Lu]Lu-PSMA-617 (90.87%). [⁶⁸Ga]Ga-LNC1011 PET/CT scans of patients with metastatic castration-resistant prostate cancer identified as many lesions as [⁶⁸Ga]Ga-PSMA-11 did, confirming its diagnostic efficacy. <b>Conclusion:</b> ⁶⁸Ga/¹⁷⁷Lu-LNC1011, characterized by high tumor uptake and retention along with timely clearance from normal organs and tissues, thus emerges as a promising single-molecule theranostic radioligand.