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Published on: April 25, 2025
Triphosgene-free solid-phase synthesis of urea-containing PSMA-targeting peptides for radiotheranostics: a
Gemma E Douglas1,2, Madhusudan Vyas3,4, Iman Kavianinia1,2,5
1School of Biological Sciences, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand. I.kavianinia@auckland.ac.nz.
Abstract:
Prostate-specific membrane antigen (PSMA) is a validated target for prostate cancer imaging and radiotherapy, with most high-affinity ligands incorporating the lysine-urea-glutamate (KuE) pharmacophore. Despite emerging triphosgene-free approaches, current synthetic strategies still largely rely on hypertoxic triphosgene for asymmetric urea formation. Herein, we report a comparative evaluation of triphosgene-free acyl-transfer reagents for on-resin KuE formation under solid-phase peptide synthesis (SPPS) conditions. Among the reagents examined, 1,1'-carbonyldiimidazole (CDI) emerged as the most effective, enabling near-quantitative urea formation under mild, SPPS-compatible conditions. Application of the optimised CDI-mediated protocol on TentaGel® resin bearing an HMPB linker enabled efficient fully solid-phase assembly of PSMA-617 in >80% crude purity and 31% isolated yield. Purified PSMA-617 was radiolabelled with 68Ga in >99% radiochemical purity, confirming chemical integrity. Additionally, the PSMA-I&T backbone and four PSMA-617 analogues were synthesised in high crude purities, demonstrating rapid on-resin ligand construction for structure-activity relationship (SAR) studies.
Insights
Researchers developed a safer, triphosgene-free method for synthesizing prostate-specific membrane antigen (PSMA) ligands. This solid-phase peptide synthesis approach using 1,1'-carbonyldiimidazole (CDI) efficiently produces PSMA-targeting agents for cancer therapy.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Radiopharmaceutical Chemistry
Background:
- Prostate-specific membrane antigen (PSMA) is a key target for prostate cancer diagnostics and therapeutics.
- High-affinity PSMA ligands often utilize the lysine-urea-glutamate (KuE) pharmacophore.
- Existing synthetic routes frequently employ toxic triphosgene for urea formation, necessitating safer alternatives.
Purpose of the Study:
- To evaluate triphosgene-free acyl-transfer reagents for on-resin KuE formation during solid-phase peptide synthesis (SPPS).
- To establish a mild and efficient SPPS protocol for constructing PSMA-targeting ligands.
Main Methods:
- Comparative analysis of various triphosgene-free acyl-transfer reagents for asymmetric urea formation under SPPS conditions.
- Optimization of the 1,1'-carbonyldiimidazole (CDI)-mediated protocol on TentaGel® resin with an HMPB linker.
- Synthesis and radiolabeling of PSMA-617 and related analogues with Gallium-68 (68Ga).
Main Results:
- 1,1'-carbonyldiimidazole (CDI) proved most effective, achieving near-quantitative urea formation under mild, SPPS-compatible conditions.
- Optimized CDI protocol enabled efficient, fully solid-phase assembly of PSMA-617 with >80% crude purity and 31% isolated yield.
- 68Ga radiolabeling of PSMA-617 yielded >99% radiochemical purity, confirming integrity. PSMA-I&T and analogues were also synthesized efficiently.
Conclusions:
- A novel, triphosgene-free CDI-mediated SPPS method facilitates efficient synthesis of PSMA-targeting ligands.
- This approach enables rapid on-resin construction of PSMA ligands for structure-activity relationship (SAR) studies and potential therapeutic development.
- The optimized protocol offers a safer and effective alternative for producing PSMA-based radiopharmaceuticals.
