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

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

doi:10.3390/molecules21060817

Zhide Guo, Zhide Guo + Show 11 more

Open Access

https://doi.org/10.3390/molecules21060817

Copy DOI

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 99mTc using tricine and trisodium triphenylphosphine-3,3′,3″-trisulfonate (TPPTS) as coligands (99mTc-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 99mTc-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 99mTc-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.

Highlights

The realization of accurate early detection of tumors requires the use of efficient and safe molecular imaging probes
Transitional product D0.5 was synthesized from the starting material propynylamine (D0 ) using the same method as the Michael addition of primary amines with methyl acrylate
D1 was synthesized from D0.5 using the same method used for amidation of methyl ester groups with a large molar excess of ethylenediamine [17,18,19]

Summary

Introduction

The realization of accurate early detection of tumors requires the use of efficient and safe molecular imaging probes. One of the rational ligands is FA, which is a stable, inexpensive, and non-immunogenic vitamin (Mw = 441 Da). This ligand provides high tumor binding affinity and better tumor uptake for its corresponding radiotracers because of the enrichment of the folate receptor (FR) on the surface of many many tumors (e.g., ovarian, breast, colorectal, endometrial and renal carcinomas) [1,2,3]. In the field of folate-based radiopharmaceuticals, over the years, several probes for positron emission tomography (PET) or single-photon emission computed tomography (SPECT) have attracted significant interest, and become important tools in molecular imaging [4,5,6].

Methods

Results

Conclusion