68Ga-Chelation and comparative evaluation of N,N′-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid (HBED-CC) conjugated NGR and RGD peptides as tumor targeted molecular imaging probes

Abstract

Peptides containing RGD and NGR motifs display high affinity towards tumor vasculature molecular markers, integrin α_vβ₃ and CD13 receptors, respectively. In the present study, RGD and NGR peptides were conjugated with the novel acyclic chelator N,N′-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid (HBED-CC) for radiolabeling with ⁶⁸Ga. The radiotracers [⁶⁸Ga-HBED-CC-c(NGR)] and [⁶⁸Ga-HBED-CC-c(RGD)] were quite hydrophilic with respective log P values being −2.8 ± 0.14 and −2.1 ± 0.17. ⁶⁸Ga-HBED-CC-c(RGD) displayed a significantly higher (p < 0.05) uptake in murine melanoma B16F10 tumors as compared to ⁶⁸Ga-HBED-CC-c(NGR) indicating its higher specificity towards integrin α_vβ₃-positive tumors. The two radiotracers showed similar uptake in CD13-positive human fibrosarcoma HT-1080 tumor xenografts (∼1.5 ± 0.2% ID g⁻¹). The tumor uptake of the two radiotracers was significantly reduced (p < 0.05) in both animal models during blocking studies. The tumor-to-blood ratio was observed to be ∼2–2.5 for the two radiotracers, whereas the tumor-to-muscle ratio was significantly higher (p < 0.005) for ⁶⁸Ga-HBED-CC-c(RGD) in the two animal models. The two radiotracers ⁶⁸Ga-HBED-CC-c(NGR) and ⁶⁸Ga-HBED-CC-c(RGD) exhibited renal excretion with rapid clearance from blood and other non-target organs. Thus, ⁶⁸Ga-chelated HBED-CC conjugated NGR and RGD peptides expressed features conducive towards development as tumor targeted molecular imaging probes. This study further opens avenues for the successful conjugation of different peptides with the acyclic chelator HBED-CC and expansion of ⁶⁸Ga-based radiopharmaceuticals.