Synthesis and Evaluation of (99m)Tc-Labeled Dimeric Folic Acid for FR-Targeting

Zhide Guo; Mengna Gao; Manli Song; Changrong Shi; Pu Zhang; Duo Xu; Linyi You; Rongqiang Zhuang; Xinhui Su; Ting Liu; Jin Du; Xianzhong Zhang

doi:10.3390/molecules21060817

Synthesis and Evaluation of (99m)Tc-Labeled Dimeric Folic Acid for FR-Targeting

Molecules. 2016 Jun 22;21(6):817. doi: 10.3390/molecules21060817.

Authors

Zhide Guo^{1

2}, Mengna Gao³, Manli Song⁴, Changrong Shi⁵, Pu Zhang⁶, Duo Xu⁷, Linyi You⁸, Rongqiang Zhuang⁹, Xinhui Su¹⁰, Ting Liu¹¹, Jin Du¹², Xianzhong Zhang¹³

Affiliations

¹ Department of Isotopes, China Institute of Atomic Energy, P. O. Box 2108, Beijing 102413, China. [email protected].
² 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. [email protected].
³ 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. [email protected].
⁴ 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. [email protected].
⁵ 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. [email protected].
⁶ 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. [email protected].
⁷ 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. [email protected].
⁸ 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. [email protected].
⁹ 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. [email protected].
¹⁰ Department of Nuclear Medicine, Zhongshan Hospital Affiliated of Xiamen University, Hubin South Road, Xiamen 361004, China. [email protected].
¹¹ 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. [email protected].
¹² Department of Isotopes, China Institute of Atomic Energy, P. O. Box 2108, Beijing 102413, China. [email protected].
¹³ 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. [email protected].

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.

Keywords: SPECT imaging; click reaction; dimeric folic acids; folate receptor; molecular imaging.

MeSH terms

Animals
Cell Line, Tumor
Folate Receptor 1 / antagonists & inhibitors*
Folate Receptor 1 / chemistry
Folate Receptor 1 / metabolism
Folic Acid / chemistry
Folic Acid / metabolism*
Humans
Mice
Neoplasms / drug therapy*
Octreotide / analogs & derivatives
Octreotide / chemistry
Organophosphorus Compounds / chemistry
Organotechnetium Compounds / chemistry
Radiopharmaceuticals / chemistry
Sulfonic Acids / chemistry
Technetium / chemistry*
Tissue Distribution

Substances

Folate Receptor 1
Organophosphorus Compounds
Organotechnetium Compounds
Radiopharmaceuticals
Sulfonic Acids
technetium Tc 99m-tricine-hydrazinonicotinyl-Phe(1)-Tyr(3)-octreotide
triphenylphosphine-3,3',3''-trisulfonic acid
Technetium
Folic Acid
Octreotide