Development of a novel 18F-labeled NGR peptide via bioorthogonal click chemistry for PET imaging of CD13 receptor expression

440 Objectives Noninvasive imaging of CD13 receptor in living subjects is of particular interest for both CD13-targeted cancer diagnosis and treatment. In this study, we radiolabeled NGR peptides with 18F via bioorthogonal click chemistry. The resulting PET probe (18F-CNGR2) was subsequently subject to in vitro and in vivo evaluations. Methods The dimeric NGR peptide (NGR2) was conjugated with an alkyne-containing PEG unit to provide a precursor, which was then mixed with an 18F-labeled azide moiety (18F-N3) to afford 18F-CNGR2 via catalyst-free click chemistry. The diagnostic value of 18F-CNGR2 was evaluated in CD13-positive HT-1080 and CD13-negative MCF-7 mouse xenografts by static PET imaging. The whole-body biodistribution and radiation dosimetry estimation for 18F-CNGR2 were further conducted in non-human primates. Results The total synthesis time for 18F-CNGR2 was about 120 min. The decay-corrected radiochemical yield was 25±4% (n = 8). For PET study, 18F-CNGR2 displayed favorable in vivo performance in terms of good tumor uptake and retention in HT-1080 tumor mouse xenografts. 18F-CNGR2 excreted predominantly through the renal route with most radioactivity in nontarget tissues cleared at 2 h pi. Tracer uptake in the HT-1080 tumor, MCF-7 tumor, kidneys, liver, and muscle was 2.98±0.26, 0.45±0.32, 1.35±0.53, 1.02±0.24, and 0.14±0.02%ID/g, respectively. The target specificity of 18F-CNGR2 was accomplished by a blocking study with unlabeled NGR peptide. In addition, time-activity data were obtained by serial, whole-body PET for normal cynomolgus monkeys following i.v. injection of 18F-CNGR2. Conclusions A novel 18F-labeled dimeric NGR peptide has been successfully developed for PET imaging of CD13 expression. Convenient preparation, high CD13 specificity in mouse tumor xenografts, and favorable excretion profile in non-human primates warrant the translation of 18F-CNGR2 into clinical investigations. Research Support This work was supported by the USC Department of Radiology, the Major Program of National Natural Science Foundation of China (Grant No. 81230033), the National Basic Research and Development Program of China (Grant No. 2011CB707704), and the Major Research Instrumentation Program of National Natural Science Foundation of China (Grant No. 81227901).