Radiolabeled new somatostatin analogs conjugated to DOMA chelator used as targeted tumor imaging agent: synthesis and radiobiological evaluation

Several receptor-specific radiopeptides have been developed and effective in the diagnosis of malignant diseases. Among them, somatostatin receptor (SSTR) scintigraphy with In-111-DTPA-octreotide has become a tumor diagnostic radiopharmaceutical in nuclear medicine. However, it suffers some drawbacks concerning the imaging properties and elevated radiation burden of In-111. Here, we report the synthesis of radiolabeled two new octapeptides with improved uptake in SSTR2-positive tumors in comparison with Tc-99m-HYNIC-Tyr(3)-octreotide (HYNIC-TOC). Octapeptides were synthesized in high yield by Fmoc solid-phase synthesis and coupling the macrocyclic chelator DOMA(1,4,7-Tri-Boc-10-(carboxymethyl)-1,4,7,10-tetraazocyclododecane-1-yl-monoacetic acid) to these peptides for Tc-99m labeling. New peptides DOMA-Asn(3)-octreotate(DOMA-AATE) and DOMA-Pro(3)-octreotate(DOMA-PATE) were purified, characterized by RP-HPLC, MALDI-mass, H-1-NMR, C-13-NMR. Labeling was performed by SnCl2 method to get products with excellent radiochemical purity (97 %). Radiopeptides were found to be substantially stable under physiological condition for 24 h. Internalization and receptor-binding studies were determined in somatostatin receptor-expressing C6-glioma cell line and rat brain cortex membrane and the results compared with HYNIC-TOC as standard. The IC50 values of Tc-99m-DOMA-AATE(1.10 +/- A 0.48 nM) and Tc-99m-DOMA-PATE(1.76 +/- A 0.06 nM) showed high affinity binding for SSTR2 receptor and they internalized rapidly in C6 cells. Biodistribution and imaging studies were performed in C6 tumor-bearing rat under gamma camera showing significant uptake in kidney, urine and C6 tumor. Radiopeptides exhibited fast blood clearance and rapid elimination through the urinary systems. However, Tc-99m-DOMA-AATE exhibited the highest tumor to muscle and tumor to blood uptake ratios among three. These favorable characteristics validate Tc-99m-DOMA-AATE as a more promising Tc-99m-radiotracer than Tc-99m-DOMA-PATE, Tc-99m-HYNIC-TOC for SSTR2-positive tumor scintigraphy.