P2X7 receptor-specific radioligand 18F-FTTM for atherosclerotic plaque PET imaging

Zhequan Fu; Qingyu Lin; Zhan Xu; Yanzhao Zhao; Yuan Cheng; Dai Shi; Wenhui Fu; Tingting Yang; Hongcheng Shi; Dengfeng Cheng

doi:10.1007/s00259-022-05689-w

P2X7 receptor-specific radioligand ¹⁸F-FTTM for atherosclerotic plaque PET imaging

Eur J Nucl Med Mol Imaging. 2022 Jul;49(8):2595-2604. doi: 10.1007/s00259-022-05689-w. Epub 2022 Jan 20.

Authors

Zhequan Fu^#^{1

2

3}, Qingyu Lin^#^{1

2

3}, Zhan Xu^{1

2

3}, Yanzhao Zhao^{1

2

3}, Yuan Cheng^{1

2

3}, Dai Shi^{1

2

3}, Wenhui Fu^{1

2

3}, Tingting Yang^{1

2

3}, Hongcheng Shi^{4

5

6}, Dengfeng Cheng^{7

8

9}

Affiliations

¹ Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China.
² Institute of Nuclear Medicine, Fudan University, Shanghai, 200032, China.
³ Shanghai Institute of Medical Imaging, Shanghai, 200032, China.
⁴ Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China. shi.hongcheng@zs-hospital.sh.cn.
⁵ Institute of Nuclear Medicine, Fudan University, Shanghai, 200032, China. shi.hongcheng@zs-hospital.sh.cn.
⁶ Shanghai Institute of Medical Imaging, Shanghai, 200032, China. shi.hongcheng@zs-hospital.sh.cn.
⁷ Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China. cheng.dengfeng@zs-hospital.sh.cn.
⁸ Institute of Nuclear Medicine, Fudan University, Shanghai, 200032, China. cheng.dengfeng@zs-hospital.sh.cn.
⁹ Shanghai Institute of Medical Imaging, Shanghai, 200032, China. cheng.dengfeng@zs-hospital.sh.cn.

^# Contributed equally.

PMID: 35048153
DOI: 10.1007/s00259-022-05689-w

Abstract

Purpose: P2X7 receptors have been considered as a promising biomarker for vulnerable atherosclerotic plaques, which are highly expressed by that instability-associated factors such as macrophages. Thus, we aim to investigate the feasibility of using specific P2X7-targeted ¹⁸F-labeled tracer ¹⁸F-FTTM ((2-chloro-3-[¹⁸F]fluorophenyl)[1,4,6,7-tetrahydro-1-(2-pyrimidinyl)-5H-1,2,3-triazolo[4,5-c]pyridin-5-yl]methanone) for PET study of vulnerable atherosclerotic plaques identification.

Method: The radioligand ¹⁸F-FTTM was achieved based on the copper-mediated radiofluorination of arylstannane. In vitro and in vivo experiments were performed to verify the biochemical properties. Dynamic ¹⁸F-FTTM Micro-PET/CT imaging was performed for 1 h on ApoE^-/- mice (10, 20, 30 weeks on high-fat diet) and wild-type C57BL/6 J mice on normal diet. Ex vivo PET imaging was conducted to verify the specificity of the radioligand. Serum inflammatory cytokines, lipids, and lipoproteins profiles were detected by ELISA. The lipid distribution and morphology of plaques were evaluated by Oil Red O, HE, Masson, and immunofluorescence stainings.

Results: ¹⁸F-FTTM was afforded with decay-corrected radiochemical yields of 5-10%, specific activity of 269-320 MBq/nmol (n = 8, EOS), and radiochemical purity of above 99%. ¹⁸F-FTTM showed excellent stability in vitro, rapid blood clearance in mice, good affinity to RAW264.7 cells. We observed an increase in both in vivo and ex vivo imagings as disease progressed, and the imaging signatures correlated with histopathological features. Furthermore, compared with ¹⁸F-FDG imaging, the SUV_max values of ¹⁸F-FTTM at the aortic arch of ApoE^-/- mice of high-fat feeding for 20 and 30 weeks were 43% and 53% higher than those of the control group, respectively.

Conclusion: We innovatively apply a new type P2X7-targeted PET probe (¹⁸F-FTTM) to identify vulnerable atherosclerotic plaques, to detect the inflammatory response of atherosclerosis, and to provide a powerful non-invasive method for the diagnosis of atherosclerotic lesions and new drug screening for accurate treatment.

Keywords: 18F-labeled; ApoE−/−; P2X7 receptors; Positron emission tomography; Vulnerable atherosclerotic plaques.

MeSH terms

Animals
Apolipoproteins E
Atherosclerosis* / diagnostic imaging
Humans
Mice
Mice, Inbred C57BL
Plaque, Atherosclerotic* / diagnostic imaging
Positron Emission Tomography Computed Tomography
Positron-Emission Tomography
Receptors, Purinergic P2X7

Substances

Apolipoproteins E
Receptors, Purinergic P2X7