title: AMD3100: A Versatile Platform for CXCR4 Targeting (68)Ga-Based Radiopharmaceuticals.
abstract: CXCR4 is a G protein-coupled receptor (GPCR), which is overexpressed in numerous diseases, particularly in multiple cancers. Therefore, this receptor represents a valuable target for imaging and therapeutic purposes. Among the different approaches, which were developed for CXCR4 imaging, a CXCR4 antagonist biscyclam system (AMD3100, also called Mozobil), currently used in the clinic for the mobilization of hematopoietic stem cells, was radiolabeled with different radiometals such as (62)Zn, (64)Cu, (67)Ga, or (99m)Tc. However, cyclam is not an ideal chelator for most of these radiometals, and could lead to the release of the radionuclide in vivo. In the current study, a new family of CXCR4 imaging agents is presented, in which AMD3100 is used as a carrier for specific delivery of an imaging reporter, i.e., a (68)Ga complex for PET imaging. AMD3100 was functionalized on the phenyl moiety with different linkers, either ethylenediamine or diamino-polyethylene glycol 3 (PEG3). The resulting AMD3100 analogues were further coupled with two different chelators, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1-glutaric acid-4,7-acetic acid (NODAGA). Five potential CXCR4 targeting agents were obtained. The derived AMD3100-based ligands were labeled with (68)Ga, highlighting the influence of the spacer nature on the (68)Ga-labeling yield. The lipophilic character of the different systems was also investigated, as well as their affinity for the CXCR4 receptor. The most promising compound was further evaluated in vivo in H69 tumor xenografts by biodistribution and PET imaging studies, validating the proof of principle of our concept.
authors.affiliation: Institut de Chimie Moléculaire de l'Université de Bourgogne, UMR6302, CNRS, Université Bourgogne Franche-Comté , F-21000 Dijon, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Poty
authors.affiliation: German Cancer Consortium (DKTK) , Heidelberg 69120, Germany.|Department of Nuclear medicine, University Hospital Freiburg , Freiburg 79106, Germany.|German Cancer Research Center (DKFZ) , Heidelberg 69120, Germany.
authors.forename: Eleni
authors.initials: E
authors.lastname: Gourni
authors.affiliation: Institut de Chimie Moléculaire de l'Université de Bourgogne, UMR6302, CNRS, Université Bourgogne Franche-Comté , F-21000 Dijon, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Désogère
authors.affiliation: CheMatech , 9 Av. Alain Savary, BP 47870, 21000 Dijon cedex, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Boschetti
authors.affiliation: Institut de Chimie Moléculaire de l'Université de Bourgogne, UMR6302, CNRS, Université Bourgogne Franche-Comté , F-21000 Dijon, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Goze
authors.affiliation: Department of Nuclear medicine, University Hospital Freiburg , Freiburg 79106, Germany.
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
authors.affiliation: Institut de Chimie Moléculaire de l'Université de Bourgogne, UMR6302, CNRS, Université Bourgogne Franche-Comté , F-21000 Dijon, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Denat
mesh_terms: D001596:Benzylamines; D000080027:Cyclams; D005710:Gallium Radioisotopes / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
chemical_list: D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D005710:Gallium Radioisotopes; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor