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


CONCLUSIONS
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.
Centre de Recherches en Cancérologie Nantes-Angers (CRCNA), Unité INSERM 892-CNRS 6299, 8 quai Moncousu, BP 70721 44007 Nantes Cedex, France.
Mathieu
M
Frindel
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.
Nathalie
N
Camus
Centre de Recherches en Cancérologie Nantes-Angers (CRCNA), Unité INSERM 892-CNRS 6299, 8 quai Moncousu, BP 70721 44007 Nantes Cedex, France.
Aurore
A
Rauscher
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.
Mickaël
M
Bourgeois
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.
Cyrille
C
Alliot
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.
Louisa
L
Barré
Centre de Recherches en Cancérologie Nantes-Angers (CRCNA), Unité INSERM 892-CNRS 6299, 8 quai Moncousu, BP 70721 44007 Nantes Cedex, France.
Jean-François
JF
Gestin
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.
Raphaël
R
Tripier
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.
Alain
A
Faivre-Chauvet
D000818:Animals; D001692:Biological Transport; D003301:Copper Radioisotopes; D004355:Drug Stability; D005260:Female; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D007553:Isotope Labeling / Q000379:methods*; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D057054:Molecular Imaging / Q000379:methods*; D010641:Phenotype; D010848:Picolinic Acids / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution
D003301:Copper Radioisotopes; C000593477:HTE1PA compound; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D010848:Picolinic Acids; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C024560:cyclam
Chelating agents; Copper radioisotopes; Cyclam; DOTA; Metabolism; Radiopharmaceuticals