Effect of Macro-Cyclic Bifunctional Chelators DOTA and NODAGA on Radiolabeling andIn VivoBiodistribution of Ga-68 Cyclic RGD Dimer

Introduction: The advent of the Germanium-68 (Ge-68)/Gallium-68 (Ga-68) generator has contributed enormously to a plethora of molecular imaging approaches for in vivo identification of tumor characteristics. The present study compares the effect of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane,1-gluteric acid-4,7-acetic acid (NODAGA) bifunctional chelators on radiolabeling of arginine-glycine-aspartic acid (RGD) dimer, an antagonist of integrin α_vβ₃ with Ga-68 and their biodistribution in C57BL/6 mice bearing melanoma and in patients with breast carcinoma. Methods: Radiolabeling parameters for DOTA-(RGD)₂ and NODAGA-(RGD)₂ with Ga-68 were optimized in-house. After quality control procedures, preclinical studies were done in C57BL/6 mice bearing melanoma. The percent radioactivity associated with per gram of various organs and tumor (% ID/g) was analyzed. Positron emission tomography-computed tomography patient imaging was performed in clinically diagnosed locally advanced breast carcinoma patients (n = 30). The uptake of various organs and lesions for both radiotracers was compared. Results: Radiolabeling yield >95% was obtained by heating 15-20 μg of peptide at 95°C for 5-10 min and 3.5-4.0 reaction pH. NODAGA-(RGD)₂ could also be radiolabeled at room temperature, but 40-50 μg peptide was required. Animal biodistribution study revealed the kidney as the major excretory organ for both the radiotracers. Maximum counts were observed in tumor at 45 min. During the clinical study, liver, spleen, bilateral brain ventricles, salivary glands, and intestines were the organs with physiological uptake of both Ga-68-DOTA-(RGD)₂ and Ga-68 NODAGA-(RGD)₂. The major excretory route was through kidneys. All primary lesions were picked by both the radiotracers. Additionally, in 5 patients, metastatic lesions were also picked up. Conclusion: DOTA- and NODAGA-chelated RGD₂ were successfully radiolabeled with Ga-68. Good tumor to background contrast exhibited by Ga-68-DOTA-(RGD)₂ and Ga-68 NODAGA-(RGD)₂ in both preclinical and clinical studies suggested that both radiotracers can be used as potential molecular tools for imaging angiogenesis.