title: Synthesis and Evaluation of (99m)Tc-Labeled Dimeric Folic Acid for FR-Targeting.
abstract: The folate receptor (FR) is overexpressed in a wide variety of human tumors. In our study, the multimeric concept was used to synthesize a dimeric folate derivative via a click reaction. The novel folate derivative (HYNIC-D₁-FA₂) was radiolabeled with (99m)Tc using tricine and trisodium triphenylphosphine-3,3',3″-trisulfonate (TPPTS) as coligands ((99m)Tc-HYNIC-D₁-FA₂) and its in vitro physicochemical properties, ex vivo biodistribution and in vivo micro-SPECT/CT imaging as a potential FR targeted agent were evaluated. It is a hydrophilic compound (log P = -2.52 ± 0.13) with high binding affinity (IC50 = 19.06 nM). Biodistribution in KB tumor-bearing mice showed that (99m)Tc-HYNIC-D₁-FA₂ had high uptake in FR overexpressed tumor and kidney at all time-points, and both of them could obviously be inhibited when blocking with free FA in the blocking studies. From the in vivo micro-SPECT/CT imaging results, good tumor uptake of (99m)Tc-HYNIC-D₁-FA₂ was observed in KB tumor-bearing mice and it could be blocked obviously. Based on the results, this new radiolabeled dimeric FA tracer might be a promising candidate for FR-targeting imaging with high affinity and selectivity.
authors.affiliation: Department of Isotopes, China Institute of Atomic Energy, P. O. Box 2108, Beijing 102413, China. guozhide0518@gmail.com.|Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiang'an South Rd, Xiamen 361102, China. guozhide0518@gmail.com.
authors.forename: Zhide
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiang'an South Rd, Xiamen 361102, China. 18037005951@163.com.
authors.forename: Mengna
authors.initials: M
authors.lastname: Gao
authors.affiliation: Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiang'an South Rd, Xiamen 361102, China. songmanli199142@126.com.
authors.forename: Manli
authors.initials: M
authors.lastname: Song
authors.affiliation: Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiang'an South Rd, Xiamen 361102, China. changrongshi2016@yahoo.com.
authors.forename: Changrong
authors.initials: C
authors.lastname: Shi
authors.affiliation: Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiang'an South Rd, Xiamen 361102, China. 18811471208@126.com.
authors.forename: Pu
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiang'an South Rd, Xiamen 361102, China. 13164604466@163.com.
authors.forename: Duo
authors.initials: D
authors.lastname: Xu
authors.affiliation: Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiang'an South Rd, Xiamen 361102, China. youly01@sina.com.
authors.forename: Linyi
authors.initials: L
authors.lastname: You
authors.affiliation: Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiang'an South Rd, Xiamen 361102, China. zhuangrongqiang@126.com.
authors.forename: Rongqiang
authors.initials: R
authors.lastname: Zhuang
authors.affiliation: Department of Nuclear Medicine, Zhongshan Hospital Affiliated of Xiamen University, Hubin South Road, Xiamen 361004, China. suxinhuii@163.com.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Su
authors.affiliation: Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiang'an South Rd, Xiamen 361102, China. tingliu20072008@yahoo.com.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Isotopes, China Institute of Atomic Energy, P. O. Box 2108, Beijing 102413, China. dujin@china-isotope.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Du
authors.affiliation: Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiang'an South Rd, Xiamen 361102, China. zhangxzh@xmu.edu.cn.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058975:Folate Receptor 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005492:Folic Acid / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D015282:Octreotide / Q000031:analogs & derivatives / Q000737:chemistry; D009943:Organophosphorus Compounds / Q000737:chemistry; D015609:Organotechnetium Compounds / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000737:chemistry; D013451:Sulfonic Acids / Q000737:chemistry; D013667:Technetium / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D058975:Folate Receptor 1; D009943:Organophosphorus Compounds; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D013451:Sulfonic Acids; C415944:technetium Tc 99m-tricine-hydrazinonicotinyl-Phe(1)-Tyr(3)-octreotide; C400058:triphenylphosphine-3,3',3''-trisulfonic acid; D013667:Technetium; D005492:Folic Acid; D015282:Octreotide
keywords: SPECT imaging; click reaction; dimeric folic acids; folate receptor; molecular imaging