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Objectives

Triazacyclononane-phosphinate chelators (TRAP) allow for ⁶⁸Ga-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 ⁶⁸Ga labeling properties and the preclinical characterization of the first two NOPO conjugates with peptidic receptor ligands.

Methods

Fully characterized NOPO was labeled with ⁶⁸Ga using non-purified eluate of an SnO₂-based ⁶⁸Ge/⁶⁸Ga generator. Selectivity for ⁶⁸Ga 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 ⁶⁸Ga-NOPO-RGD and ⁶⁸Ga-NOPO-NOC was performed on SCINTOMICS Gallelut⁺ system. Biodistribution studies and preclinical PET imaging with ⁶⁸Ga-NOPO-RGD and ⁶⁸Ga-NOPO-NOC were done using nude mice with M21/M21L and AR42J xenografts, respectively.

Results

⁶⁸Ga labeling of NOPO conjugates proceeds rapidly and efficiently at r.t. NOPO possesses high selectivity for ⁶⁸Ga in the presence of high concentrations of Zn²⁺, Cu²⁺, Fe³⁺, Al³⁺, Ti⁴⁺, and Sn⁴⁺. No incorporation of ⁶⁸Ge was observed. ⁶⁸Ga-NOPO-RGD was prepared with specific activities > 5000 GBq/µmol. No loss of ⁶⁸Ga was observed upon competition with 0.25 M EDTA, in PBS at 37 °C, and in vivo. M21 tumor uptake of ⁶⁸Ga-NOPO-RGD was comparable to that of ⁶⁸Ga-NODAGA-RGD and ¹⁸F-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, ⁶⁸Ga-NOPO-NOC was stable in vivo, showed high tumor uptake with low background, and excretion via kidneys.

Conclusions

NOPO keeps the unique labeling properties of symmetrical TRAP chelators while allowing for straightforward monoconjugation. Its ⁶⁸Ga-labeled conjugates are fully stable and possess favorable in vivo properties. Therefore, NOPO perfectly enhances the portfolio of chelators for synthesis of ⁶⁸Ga radiopharmaceuticals

Tosin Akintewe

Publications