Preparation and Bioevaluation of Novel 99mTc-Labeled Complexes with a 2-Nitroimidazole HYNIC Derivative for Imaging Tumor Hypoxia.

Qing Ruan,Junbo Zhang,Si’an Fang,Xuran Zhang,Qianqian Gan

doi:10.3390/ph14020158

Qing Ruan, Junbo Zhang + Show 3 more

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https://doi.org/10.3390/ph14020158

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Journal: Pharmaceuticals	Publication Date: Feb 15, 2021
Citations: 6	License type: CC BY 4.0

Affiliation: Beijing Normal University

Abstract

To develop novel 99mTc-labeled single-photon emission computed tomography (SPECT) radiotracers for imaging hypoxia, a novel HYNICNM ligand (6-hydrazinonicotinamide (HYNIC) 2-nitroimidazole derivative) was designed and synthesized. It was radiolabeled with technetium-99m using tricine/trisodium triphenylphosphine-3,3′,3′′-trisulfonate (TPPTS), tricine/sodium triphenylphosphine-3-monosulfonate (TPPMS) and tricine as co-ligands to obtain [99mTc]Tc-tricine-TPPTS-HYNICNM, [99mTc]Tc-tricine-TPPMS-HYNICNM, and [99mTc]Tc-(tricine)2-HYNICNM, respectively. The three technetium-99m complexes were radiolabeled in one step with a high yield (95%) and had good stability in saline and mouse serum. In vitro cellular uptake results showed that these complexes exhibited good hypoxic selectivity. The partition coefficient indicated that they were good hydrophilic complexes, and [99mTc]Tc-tricine-TPPTS-HYNICNM displayed the highest hydrophilicity (−3.02 ± 0.08). The biodistribution in mice bearing S180 tumors showed that [99mTc]Tc-tricine-TPPTS-HYNICNM exhibited higher tumor uptake (1.05 ± 0.27% IA/g); more rapid clearance from the liver, blood, muscle, and other non-target organs; and a higher tumor/non-target ratio, especially for the tumor/liver ratio (1.95), than [99mTc]Tc-tricine-TPPMS-HYNICNM and [99mTc]Tc-(tricine)2-HYNICNM. The results of single-photon emission computed tomography (SPECT) imaging studies of [99mTc]Tc-tricine-TPPTS-HYNICNM were in accordance with the biodistribution results, which suggested that [99mTc]Tc-tricine-TPPTS-HYNICNM is a promising agent for imaging tumor hypoxia.

Highlights

Hypoxia occurs in various solid tumors when the consumption of oxygen exceeds the supply of the bloodstream with uncontrolled tumor growth
The HYNIC-containing active ester (Compound 1) was synthesized in three steps [35], and the amino derivative of 2-nitroimidazole (Compound 2) was prepared via two steps from 2-nitroimidazole [13], which are shown in the Supplementary Material in detail
The ligand, HYNICNM, was synthesized by Compound 1 and Compound 2 in one step, as shown in Scheme 1, and the final product was identified by 1 H NMR, 13 C NMR, IR, and HR-MS (Figures S3–S6), indicating that the target ligand was successfully synthesized as our proposed structure

Summary

Introduction

Hypoxia occurs in various solid tumors when the consumption of oxygen exceeds the supply of the bloodstream with uncontrolled tumor growth. It is regarded as a factor determining tumor aggressiveness, invasiveness, and therapy resistance, especially for radiotherapy and chemotherapy [1,2]. In addition to its direct impact on tumor therapy, hypoxia is associated with a number of molecular signaling pathways that influence tumor behavior. The gold standard for detecting tumor hypoxia is the oxygen needle electrode method, which can obtain relatively accurate measurement results of local oxygen concentrations and involves the insertion of a fine needle electrode into the accessible region in the tumor, which is invasive [6,7]. Nuclear imaging techniques, including single-photon emission computed tomography (SPECT) and positron emission tomography (PET) with hypoxia imaging agents, are more favorable for the clinical detec-

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