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

Abstract

Several receptor-specific radiopeptides have been developed and effective in the diagnosis of malignant diseases. Among them, somatostatin receptor (SSTR) scintigraphy with (111)In-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 (111)In. Here, we report the synthesis of radiolabeled two new octapeptides with improved uptake in SSTR2-positive tumors in comparison with (99m)Tc-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 (99m)Tc labeling. New peptides DOMA-Asn(3)-octreotate(DOMA-AATE) and DOMA-Pro(3)-octreotate(DOMA-PATE) were purified, characterized by RP-HPLC, MALDI-mass, (1)H-NMR, (13)C-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 (99m)Tc-DOMA-AATE(1.10 ± 0.48 nM) and (99m)Tc-DOMA-PATE(1.76 ± 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, (99m)Tc-DOMA-AATE exhibited the highest tumor to muscle and tumor to blood uptake ratios among three. These favorable characteristics validate (99m)Tc-DOMA-AATE as a more promising (99m)Tc-radiotracer than (99m)Tc-DOMA-PATE, (99m)Tc-HYNIC-TOC for SSTR2-positive tumor scintigraphy.

The construction of the multifunctional targeting ursolic acids liposomes and its apoptosis effects to C6 glioma stem cells

“…Chemotherapy is considered as one of the major ways to treat cancer in clinic. Nowadays, the main problems that limit the clinical application of normal anti-cancer drugs were their low concentration at tumor sites and severe side effects [ 17 , 18 ]. So the targeting delivery of anti-cancer drugs is now a focus in scientific research.…”

Study of the 99mTc‐labeling conditions of 6‐hydrazinonicotinamide‐conjugated peptides from a new perspective: Introduction to the term radio‐stoichiometry

“…Therefore, these natural neuropeptides are not suitable for in vivo applications. 33 A large variety of SST analogs with enhanced resistance to in vivo enzymatic degradation and biological activity have been developed to overcome this problem. Stable SST analogs, namely, lanreotide, octreotide, vapreotide (RC-160), and others, are the most frequently used diagnostic peptide radiopharmaceuticals.…”

“…Both natural SST‐14 and SST‐28 can be bound with high affinity to five different receptor subtypes (sstr 1 –sstr 5 ), but they have a short plasma half‐life because of rapid enzymatic degradation by endogenous peptidases. Therefore, these natural neuropeptides are not suitable for in vivo applications 33 . A large variety of SST analogs with enhanced resistance to in vivo enzymatic degradation and biological activity have been developed to overcome this problem.…”

Computed Tomographic Studies of Noncalcified Nodules Related to Neuroendocrine Lung Tumor Using 68Gallium-Tagged Somatostatin Variant for Improvement in Diagnosis: A Non-Experimental, Non-Randomized, Cross-Sectional Study

“…Because somatostatin receptors affect the expression of normal and malignant cells, or cancerous cells, research, especially in developing countries, uses the high-affinity somatostatin receptor variants in PET for imaging. With somatostatin receptor-expressing tumors, there is the possibility of improved spatial and contrast resolution of obtained scan results [ 11 ]. For patients who never underwent surgery and/or who did not respond well to typical treatments, β-emitting radionuclides-labeled somatostatin variants might be effective as directed radiotherapy, such as peptide receptor radionuclide therapy [ 4 ], as well as in the imaging of neuroendocrine tumors [ 12 ].…”