Sedigheh Rezaeianpour1, Atefeh Hajiagha Bozorgi2, Abolghasem Moghimi1, Ameneh Almasi3, Saeed Balalaie4, Sorour Ramezanpour4, Sanaz Nasoohi5, Seyed Mohammad Mazidi6, Parham Geramifar7, Ahmad Bitarafan-Rajabi8, Soraya Shahhosseini9. 1. Department of Chemistry, North Tehran Branch of Islamic Azad University, Tehran, Iran. 2. Alborz University of Medical Sciences, Karaj, Iran. 3. Department of Pharmaceutics, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 4. Peptide Chemistry Research Center, K.N. Toosi University of Technology, Tehran, Iran. 5. Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 6. Radiation Application Research School, Nuclear Science and Technology Research Institute, Tehran, Iran. 7. Research Center for Nuclear Medicine, Tehran University of Medical Sciences, Tehran, Iran. 8. Cardiovascular Interventional Research Center, Department of Nuclear Medicine, Rajaei Cardiovascular, Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran. 9. Department of Pharmaceutical Chemistry and Radiopharmacy, School of Pharmacy and PET/CT Unit, Ferdous Nuclear Medicine Center, Dr. Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Vali-e Asr Ave., Niayesh Junction, P.O. Box 14155-6153, Tehran, Iran. s_shahoseini@sbmu.ac.ir.
Abstract
PURPOSE: Many patients worldwide suffer from cardiovascular diseases for which an underlying factor is thrombosis. Devising a molecular imaging technique for early detection of thrombosis in a clinical setting is highly recommended. Because fibrin is a major constituent of clots and is present in all types of thrombi but absent in circulation, it is a highly specific and sensitive target for molecular imaging of thrombi. It is assumed that cyclization of peptides will improve the receptor binding affinity and stability of the peptide. In the present study, we have developed linear and cyclic fibrin-binding peptides for thrombus imaging and compared their biological properties. PROCEDURES: Linear HYNIC-GPRPP and cyclic HYNIC-CGPRPPC peptides were synthesized using a standard Fmoc strategy and radiolabeled with Tc-99m. The stability of the radiolabeled peptides in human plasma and their affinity for fibrin and blood clots were determined. Blood clearance and biodistribution were evaluated in rats and mice, respectively. The peptide with the highest affinity was injected to a live rabbit femoral thrombosis model, and scintigraphic images were obtained. RESULTS: In vitro studies show that peptides are stable in human plasma and have a high affinity for human fibrin. They also demonstrated fast blood clearance in rats and high thrombus uptake in the Balb/c mice femoral thrombosis model. Femoral thrombosis was visualized 30 min postinjection of cyclic peptide in a live rabbit model using single photon emission computed tomography (SPECT)/X-ray computed tomography. CONCLUSIONS: The results indicate that the cyclic peptide is a promising agent for molecular imaging of fibrin using SPECT.
PURPOSE: Many patients worldwide suffer from cardiovascular diseases for which an underlying factor is thrombosis. Devising a molecular imaging technique for early detection of thrombosis in a clinical setting is highly recommended. Because fibrin is a major constituent of clots and is present in all types of thrombi but absent in circulation, it is a highly specific and sensitive target for molecular imaging of thrombi. It is assumed that cyclization of peptides will improve the receptor binding affinity and stability of the peptide. In the present study, we have developed linear and cyclic fibrin-binding peptides for thrombus imaging and compared their biological properties. PROCEDURES: Linear HYNIC-GPRPP and cyclic HYNIC-CGPRPPC peptides were synthesized using a standard Fmoc strategy and radiolabeled with Tc-99m. The stability of the radiolabeled peptides in human plasma and their affinity for fibrin and blood clots were determined. Blood clearance and biodistribution were evaluated in rats and mice, respectively. The peptide with the highest affinity was injected to a live rabbitfemoral thrombosis model, and scintigraphic images were obtained. RESULTS: In vitro studies show that peptides are stable in human plasma and have a high affinity for human fibrin. They also demonstrated fast blood clearance in rats and high thrombus uptake in the Balb/c micefemoral thrombosis model. Femoral thrombosis was visualized 30 min postinjection of cyclic peptide in a live rabbit model using single photon emission computed tomography (SPECT)/X-ray computed tomography. CONCLUSIONS: The results indicate that the cyclic peptide is a promising agent for molecular imaging of fibrin using SPECT.
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