title: Evaluation of N-[(11)C]methyl-AMD3465 as a PET tracer for imaging of CXCR4 receptor expression in a C6 glioma tumor model.
abstract: The chemokine receptor CXCR4 and its ligand CXCL12 play an important role in tumor progression and metastasis. CXCR4 receptors are expressed by many cancer types and provide a potential target for treatment. Noninvasive detection of CXCR4 may aid diagnosis and improve therapy selection. It has been demonstrated in preclinical studies that positron emission tomography (PET) with a radiolabeled small molecule could enable noninvasive monitoring of CXCR4 expression. Here, we prepared N-[(11)C]methyl-AMD3465 as a new PET tracer for CXCR4. N-[(11)C]Methyl-AMD3465 was readily prepared by N-methylation with [(11)C]CH3OTf. The tracer was obtained in a 60 ± 2% yield (decay corrected), the purity of the tracer was >99%, and specific activity was 47 ± 14 GBq/μmol. Tracer stability was tested in vitro using liver microsomes and rat plasma; excellent stability was observed. The tracer was evaluated in rat C6 glioma and human PC-3 cell lines. In vitro cellular uptake of N-[(11)C]methyl-AMD3465 was receptor mediated. The effect of transition metal ions (Cu(2+), Ni(2+), and Zn(2+)) on cellular binding was examined in C6 cells, and the presence of these ions increased the cellular binding of the tracer 9-, 7-, and 3-fold, respectively. Ex vivo biodistribution and PET imaging of N-[(11)C]methyl-AMD3465 were performed in rats with C6 tumor xenografts. Both PET and biodistribution studies demonstrated specific accumulation of the tracer in the tumor (SUV 0.6 ± 0.2) and other CXCR4 expressing organs, such as lymph node (1.5 ± 0.2), liver (8.9 ± 1.0), bone marrow (1.0 ± 0.3), and spleen (1.0 ± 0.1). Tumor uptake was significantly reduced (66%, p < 0.01) after pretreatment with Plerixafor (AMD3100). Biodistribution data indicates a tumor-to-muscle ratio of 7.85 and tumor-to-plasma ratio of 1.14, at 60 min after tracer injection. Our data demonstrated that N-[(11)C]methyl-AMD3465 is capable of detecting physiologic CXCR4 expression in tumors and other CXCR4 expressing tissues. These results warrant further evaluation of N-[(11)C]methyl-AMD3465 as a potential PET tracer for CXCR4 receptor imaging.
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen , University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: S V
authors.initials: SV
authors.lastname: Hartimath
authors.forename: A
authors.initials: A
authors.lastname: van Waarde
authors.forename: R A J O
authors.initials: RA
authors.lastname: Dierckx
authors.forename: E F J
authors.initials: EF
authors.lastname: de Vries
mesh_terms: D000818:Animals; D001596:Benzylamines; D001932:Brain Neoplasms / Q000000981:diagnostic imaging*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D000080027:Cyclams; D005786:Gene Expression Regulation; D005910:Glioma / Q000000981:diagnostic imaging*; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics; D006801:Humans; D007477:Ions; D008024:Ligands; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D019718:Receptors, CXCR4 / Q000378:metabolism*
chemical_list: D001596:Benzylamines; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D002250:Carbon Radioisotopes; D000080027:Cyclams; D006571:Heterocyclic Compounds; D007477:Ions; D008024:Ligands; C503590:N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; D011725:Pyridines; D019718:Receptors, CXCR4; C088327:plerixafor
keywords: AMD3465; PET; cancer and metastasis; chemokine receptor 4; radiotracer; tumor imaging