Synthesis, radiolabeling, and evaluation of 68Ga-labeled aminoquinoxaline derivative as a potent PFKFB3-targeted PET tracer

Feng Chen; Yi Wu; Yixuan Ma; Honghai Yin; Feijing Su; Rui Huang; Xiaoai Wu; Qian Liu

doi:10.3389/fchem.2023.1158503

Synthesis, radiolabeling, and evaluation of 68Ga-labeled aminoquinoxaline derivative as a potent PFKFB3-targeted PET tracer

Front Chem. 2023 Mar 22:11:1158503. doi: 10.3389/fchem.2023.1158503. eCollection 2023.

Authors

Feng Chen^{1

2

3

4}, Yi Wu³, Yixuan Ma³, Honghai Yin⁵, Feijing Su⁶, Rui Huang⁷, Xiaoai Wu⁵, Qian Liu^{1

4

8

9}

Affiliations

¹ Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
² Department of Pediatric Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China.
³ Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, China.
⁴ Jiangxi Provincial Clinical Research Center for Vascular Anomalies, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China.
⁵ Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
⁶ Core Facilities of West China Hospital, Sichuan University, Sichuan, China.
⁷ Department of Neurology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, China.
⁸ Integrated Chinese and Western Medicine Institute for Children Health & Drug Innovation, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China.
⁹ Jiangxi Key Laboratory of TCM for Prevention and Treatment on Hemangioma, Nanchang, Jiangxi, China.

Abstract

Glycolysis, as a multi-step oxidation process, plays important roles in the energy supply for living cells, including malignant tumor cells. Recent studies have revealed that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (named PFKFB3), a bifunctional enzyme in glycolysis, is upregulated in a variety of malignant solid tumors and has been regarded as a potential biomarker for the diagnosis and treatment of tumor patients. Based on the structure of selective PFKFB3 inhibitors, we designed and synthesized a radio-metal radiolabeled small molecule, ⁶⁸Ga-5, which also showed potent selectivity in enzymatic and biochemical tests (with an IC₅₀ value of 12.5 nM). According to further in vitro and in vivo evaluations, ⁶⁸Ga-5 showed promising properties as a PET ligand, and selective accumulation in PFKFB3-positive tumors was observed in PET images (with max SUV values of 0.60). Our results indicated that radio-metal radiolabeled aminoquinoxaline derivative, as represented by ⁶⁸Ga-5, held the potential to be developed as selective PFKFB3-targeted PET tracers, and further investigation and optimization would also be required for this scaffold.

Keywords: PET; PET tracers; PFKFB3; inhibitors; radiolabeled compounds.

Grants and funding

The authors greatly appreciate the support for this research from the Open Project of Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education [Grant No. XN202024]; the Key Project of Natural Science Foundation of Jiangxi Province, [Grant No. 20192ACBL20005]; the Natural Science Foundation for the Youth of Jiangxi Province [Grant No. 20181BAB205052], Science and Technology Project of Traditional Chinese Medicine of Jiangxi Province [Grant No. 2021A153] and Sichuan Science and Technology Program [Grant No. 2020YJ0457]. National Science Foundation of China (No. 21602090).