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

De, Kakali, Banerjee, Indranil, Misra, Mridula
Amino acids 2015 v.47 no.6 pp. 1135-1153
binding capacity, blood, brain, chelating agents, cortex, image analysis, inhibitory concentration 50, kidneys, medicine, neoplasms, nuclear magnetic resonance spectroscopy, radiolabeling, rats, reversed-phase high performance liquid chromatography, scintigraphy, somatostatin, somatostatin receptors, urine
Several receptor-specific radiopeptides have been developed and effective in the diagnosis of malignant diseases. Among them, somatostatin receptor (SSTR) scintigraphy with ¹¹¹In-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 ¹¹¹In. Here, we report the synthesis of radiolabeled two new octapeptides with improved uptake in SSTR2-positive tumors in comparison with ⁹⁹ᵐTc-HYNIC-Tyr³-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 ⁹⁹ᵐTc labeling. New peptides DOMA-Asn³-octreotate(DOMA-AATE) and DOMA-Pro³-octreotate(DOMA-PATE) were purified, characterized by RP-HPLC, MALDI-mass, ¹H-NMR, ¹³C-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 ⁹⁹ᵐTc-DOMA-AATE(1.10 ± 0.48 nM) and ⁹⁹ᵐTc-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, ⁹⁹ᵐTc-DOMA-AATE exhibited the highest tumor to muscle and tumor to blood uptake ratios among three. These favorable characteristics validate ⁹⁹ᵐTc-DOMA-AATE as a more promising ⁹⁹ᵐTc-radiotracer than ⁹⁹ᵐTc-DOMA-PATE, ⁹⁹ᵐTc-HYNIC-TOC for SSTR2-positive tumor scintigraphy.