title: Development of a Novel PET Tracer [18F]AlF-NOTA-C6 Targeting MMP2 for Tumor Imaging.
abstract: OBJECTIVE
  The overexpression of gelatinases, that is, matrix metalloproteinase MMP2 and MMP9, has been associated with tumor progression, invasion, and metastasis. To image MMP2 in tumors, we developed a novel ligand termed [18F]AlF-NOTA-C6, with consideration that: c(KAHWGFTLD)NH2 (herein, C6) is a selective gelatinase inhibitor; Cy5.5-C6 has been visualized in many in vivo tumor models; positron emission tomography (PET) has a higher detection sensitivity and a wider field of view than optical imaging; fluorine-18 (18F) is the optimal PET radioisotope, and the creation of a [18F]AlF-peptide complex is a simple procedure.
  
  
  METHODS
  C6 was conjugated to the bifunctional chelator NOTA (1, 4, 7-triazacyclononanetriacetic acid) for radiolabeling [18F]AlF conjugation. The MMP2-binding characteristics and tumor-targeting efficacy of [18F]AlF-NOTA-C6 were tested in vitro and in vivo.
  
  
  RESULTS
  The non-decay corrected yield of [18F]AlF-NOTA-C6 was 46.2-64.2%, and the radiochemical purity exceeded 95%. [18F]AlF-NOTA-C6 was favorably retained in SKOV3 and PC3 cells, determined by cell uptake. Using NOTA-C6 as a competitive ligand, the uptake of [18F]AlF-NOTA-C6 in SKOV3 cells decreased in a dose-dependent manner. In biodistribution and PET imaging studies, higher radioactivity concentrations were observed in tumors. Pre-injection of C6 caused a marked reduction in tumor tissue uptake. Immunohistochemistry showed MMP2 in tumor tissues.
  
  
  CONCLUSIONS
  [18F]AlF-NOTA-C6 was easy to synthesize and has substantial potential as an imaging agent that targets MMP2 in tumors.
authors.affiliation: Department of Nuclear Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, 200433, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Jiangsu Institute of Nuclear Medicine, Key Laboratory of Nuclear Medicine, Ministry of Health, Wuxi, 214063, China.
authors.forename: Donghui
authors.initials: D
authors.lastname: Pan
authors.affiliation: Department of Nuclear Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, 200433, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Dazhi
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Nuclear Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, 200433, China.
authors.forename: Anyu
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Jiangsu Institute of Nuclear Medicine, Key Laboratory of Nuclear Medicine, Ministry of Health, Wuxi, 214063, China.
authors.forename: Lizhen
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Nuclear Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, 200433, China.
authors.forename: Hongdie
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Nuclear Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, 200433, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China.
authors.forename: Hongrui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Jiangsu Institute of Nuclear Medicine, Key Laboratory of Nuclear Medicine, Ministry of Health, Wuxi, 214063, China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Jiangsu Institute of Nuclear Medicine, Key Laboratory of Nuclear Medicine, Ministry of Health, Wuxi, 214063, China.
authors.forename: Runlin
authors.initials: R
authors.lastname: Yang
authors.affiliation: Jiangsu Institute of Nuclear Medicine, Key Laboratory of Nuclear Medicine, Ministry of Health, Wuxi, 214063, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.affiliation: Jiangsu Institute of Nuclear Medicine, Key Laboratory of Nuclear Medicine, Ministry of Health, Wuxi, 214063, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Nuclear Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, 200433, China.
authors.forename: Changjing
authors.initials: C
authors.lastname: Zuo
mesh_terms: D045744:Cell Line, Tumor; D005462:Fluorine Radioisotopes / Q000008:administration & dosage*; D006571:Heterocyclic Compounds / Q000008:administration & dosage*; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D008024:Ligands; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D010455:Peptides / Q000008:administration & dosage; D049268:Positron-Emission Tomography / Q000379:methods; D011854:Radiochemistry / Q000379:methods; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D008024:Ligands; D010455:Peptides; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid; D020778:Matrix Metalloproteinase 2