Abstract
<b>236</b> <h3><b>Objectives</b></h3> Triazacyclononane-phosphinate chelators (TRAP) allow for <sup>68</sup>Ga-labeling with high specific activity. To transfer the excellent labeling characteristics of TRAP to monomeric ligands, we developed the monoconjugable chelator NOPO. We report on the <sup>68</sup>Ga labeling properties and the preclinical characterization of the first two NOPO conjugates with peptidic receptor ligands. <h3><b>Methods</b></h3> Fully characterized NOPO was labeled with <sup>68</sup>Ga using non-purified eluate of an SnO<sub>2</sub>-based <sup>68</sup>Ge/<sup>68</sup>Ga generator. Selectivity for <sup>68</sup>Ga was investigated in the presence of various metal chlorides. Conjugates with c(RGDfK) (NOPO-RGD) and NaI-octreotide (NOPO-NOC) were prepared using standard peptide coupling methods. Automated production of <sup>68</sup>Ga-NOPO-RGD and <sup>68</sup>Ga-NOPO-NOC was performed on SCINTOMICS Gallelut<sup>+</sup> system. Biodistribution studies and preclinical PET imaging with <sup>68</sup>Ga-NOPO-RGD and <sup>68</sup>Ga-NOPO-NOC were done using nude mice with M21/M21L and AR42J xenografts, respectively. <h3><b>Results</b></h3> <sup>68</sup>Ga labeling of NOPO conjugates proceeds rapidly and efficiently at r.t. NOPO possesses high selectivity for <sup>68</sup>Ga in the presence of high concentrations of Zn<sup>2+</sup>, Cu<sup>2+</sup>, Fe<sup>3+</sup>, Al<sup>3+</sup>, Ti<sup>4+</sup>, and Sn<sup>4+</sup>. No incorporation of <sup>68</sup>Ge was observed. <sup>68</sup>Ga-NOPO-RGD was prepared with specific activities > 5000 GBq/µmol. No loss of <sup>68</sup>Ga was observed upon competition with 0.25 M EDTA, in PBS at 37 °C, and in vivo. M21 tumor uptake of <sup>68</sup>Ga-NOPO-RGD was comparable to that of <sup>68</sup>Ga-NODAGA-RGD and <sup>18</sup>F-Galacto-RGD. Furthermore, due to the high polarity of NOPO, the conjugate exhibited very high hydrophilicity (logP = -4.6), resulting in fast renal excretion. Similarly, <sup>68</sup>Ga-NOPO-NOC was stable in vivo, showed high tumor uptake with low background, and excretion via kidneys. <h3><b>Conclusions</b></h3> NOPO keeps the unique labeling properties of symmetrical TRAP chelators while allowing for straightforward monoconjugation. Its <sup>68</sup>Ga-labeled conjugates are fully stable and possess favorable in vivo properties. Therefore, NOPO perfectly enhances the portfolio of chelators for synthesis of <sup>68</sup>Ga radiopharmaceuticals
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