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

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Abstract

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.

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Acknowledgments

Financial support in the form of Research Associateship (Dr. Kakali De) from the Indian Council of Medical Research (ICMR), New Delhi, India, is acknowledged. The authors also gratefully acknowledge Prof. Siddhartha Roy, Director, CSIR-Indian Institute of Chemical Biology, Kolkata, India for providing infrastructure facilities. Authors sincerely acknowledge Dr. Santanu Ganguly and Mr. Bhart Sarkar of Regional Radiation Medicine Centre and Variable Energy Cyclotron Centre, Thakurpukur Cancer Centre and Welfare Home Campus, Kolkata, India, for their kind help for taking the image of tumor-bearing rats.

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The authors declare that they have no conflict of interests.

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  1. Division of Infectious Diseases and Immunology, Nuclear Medicine Department, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology, 4 Raja S C Mullick Road, Kolkata, 700032, West Bengal, India

    Kakali De, Indranil Banerjee & Mridula Misra

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  1. Kakali De
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  2. Indranil Banerjee
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  3. Mridula Misra
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Correspondence to Kakali De.

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De, K., Banerjee, I. & Misra, M. Radiolabeled new somatostatin analogs conjugated to DOMA chelator used as targeted tumor imaging agent: synthesis and radiobiological evaluation. Amino Acids 47, 1135–1153 (2015). https://doi.org/10.1007/s00726-015-1942-0

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