Mathieu Frindel1, Nathalie Camus2, Aurore Rauscher1, Mickaël Bourgeois3, Cyrille Alliot3, Louisa Barré4, Jean-François Gestin1, Raphaël Tripier5, Alain Faivre-Chauvet6. 1. Centre de Recherches en Cancérologie Nantes-Angers (CRCNA), Unité INSERM 892-CNRS 6299, 8 quai Moncousu, BP 70721 44007 Nantes Cedex, France. 2. Université de Bretagne Occidentale, UMR-CNRS 6521, SFR ScInBioS, UFR des Sciences et Techniques, 6 avenue Victor le Gorgeu, C.S. 93837, 29238 Brest Cedex 3, France. 3. Centre de Recherches en Cancérologie Nantes-Angers (CRCNA), Unité INSERM 892-CNRS 6299, 8 quai Moncousu, BP 70721 44007 Nantes Cedex, France; Cyclotron ARRONAX, 1 rue Aronnax CS 10112 44817 Saint-Herblain Cedex, France. 4. CEA-DSV-I2BM-ISTCT-Laboratoire de Développements Méthodologiques en TEP (LDM TEP), UMR 6301, Cyceron-Bd Henri Becquerel, BP 5229, 14074 Caen Cedex 5, France. 5. Université de Bretagne Occidentale, UMR-CNRS 6521, SFR ScInBioS, UFR des Sciences et Techniques, 6 avenue Victor le Gorgeu, C.S. 93837, 29238 Brest Cedex 3, France. Electronic address: Raphael.Tripier@univ-brest.fr. 6. Centre de Recherches en Cancérologie Nantes-Angers (CRCNA), Unité INSERM 892-CNRS 6299, 8 quai Moncousu, BP 70721 44007 Nantes Cedex, France. Electronic address: Alain.Faivre-Chauvet@univ-nantes.fr.
Abstract
INTRODUCTION: 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.
INTRODUCTION: 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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