Enhanced PET Imaging of SST2-Positive Tumors with Cu- and Ga-Labeled Somatostatin Antagonists: Impact of Chelating Agents

Radiolabeled somatostatin peptides have been utilized for the imaging and treatment of somatostatin receptor-positive tumors, with a focus on subtype 2. Traditionally, agonists have been used clinically, but recent findings suggest that antagonists could offer superior pharmacokinetics and tumor uptake. The study in question explores the development of four radioantagonists for PET imaging of sst2-positive tumors, focusing on the antagonist LM3 and its conjugation with different chelators.

The synthesis of the radioantagonists involved the attachment of LM3 to three distinct macrocyclic chelators, including CB-TE2A, NODAGA, and DOTA. The preparation methods varied with temperature, and the binding affinity and antagonistic properties were assessed using HEK-sst2 cells.

Results indicated that all radioantagonists exhibited the desired antagonistic behavior, with affinities influenced by the choice of chelator and radiometal. Notably, (68/nat)Ga-NODAGA-LM3 displayed the lowest half-maximal inhibitory concentration. Biodistribution studies revealed significant tumor uptake for certain radioantagonists, particularly (64)Cu- and (68)Ga-NODAGA-LM3, with rapid background clearance and slow tumor washout observed for (64)Cu-NODAGA-LM3. Tumor-to-normal tissue ratios were notably higher for (64)Cu-NODAGA-LM3 compared to (64)Cu-CB-TE2A-LM3, indicating better targeting. Small-animal PET imaging confirmed clear tumor visualization and high image contrast, especially for the NODAGA-LM3 conjugates.

The study concludes that the affinity and pharmacokinetics of somatostatin-based radioantagonists are heavily influenced by the chelator and radiometal used. The radioantagonists (64)Cu- and (68)Ga-NODAGA-LM3 and (64)Cu-CB-TE2A-LM3 are highlighted as promising candidates for clinical application due to their favorable pharmacokinetics and the high image contrast they provide in PET scans.