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Radiolabeling of HTE1PA: A new monopicolinate cyclam derivative for Cu-64 phenotypic imaging. In vitro and in vivo stability studies in mice

Abstract : HTE1PA, a monopicolinate-N-alkylated cyclam-based ligand has previously demonstrated fast complexation process, high kinetic inertness and important thermodynamic and electrochemical stability with respect to natural copper. In this work we first developed a new synthetic route to obtain HTE1PA in good yields. Then, we investigated HTE1PA chelation properties towards copper-64 and assessed in vitro and in vivo stability of the resulting compound. METHODS: Radiolabeling of HTE1PA with copper-64 was tested at different ligand concentrations in ammonium acetate medium. In vitro stability study was carried out by incubating [(64)Cu]TE1PA complex in human serum at both 37°C and 4°C; chromatographic controls were performed over 24h. Biodistribution, pharmacokinetic and hepatic metabolism of [(64)Cu]TE1PA were conducted in BALC/c mice in comparison with [(64)Cu]acetate and [(64)Cu]DOTA, used as a reference ligand. RESULTS: The promising results obtained for natural copper complexation were confirmed. HTE1PA was quantitatively radiolabeled in 15 min at room temperature. The resulting complex showed high serum stability. [(64)Cu]TE1PA induced a significant uptake in the liver and kidneys at early biodistribution time point. Nevertheless, a high speed wash out was observed at 24h leading to significantly lower uptake into the liver compared to [(64)Cu]DOTA. The metabolism study was consistent with a high resistance to transchelation as the initial uptake into liver matches with the intact form of [(64)Cu]TE1PA. CONCLUSION: Despite the partial elimination of HTE1PA - as copper-64 complex - through the hepatic route, its high selectivity for copper and its resistance to transchelation make it a promising ligand for antibody radiolabeling with either copper-64 or copper-67.
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https://hal.archives-ouvertes.fr/hal-01529578
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Submitted on : Wednesday, May 31, 2017 - 9:47:56 AM
Last modification on : Wednesday, December 18, 2019 - 3:52:06 PM

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Mathieu Frindel, Nathalie Camus, Aurore Rauscher, Mickaël Bourgeois, Cyrille Alliot, et al.. Radiolabeling of HTE1PA: A new monopicolinate cyclam derivative for Cu-64 phenotypic imaging. In vitro and in vivo stability studies in mice. Nuclear Medicine and Biology, Elsevier, 2014, 41, pp.e49 - e57. ⟨10.1016/j.nucmedbio.2013.12.009⟩. ⟨hal-01529578⟩

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