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A radioiodinated FR-β-targeted tracer with improved pharmacokinetics through modification with an albumin binder for imaging of macrophages in AS and NAFL

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The formation of advanced plaques, which is characterized by the uninterrupted aggregation of macrophages with high expression of folate receptor-β (FR-β), is observed in several concomitant metabolic syndromes. The objective of this study was to develop a novel FR-β-targeted single-photon emission computed tomography (SPECT) radiotracer and validate its application to the noninvasive detection of atherosclerosis (AS) plaque and non-alcoholic fatty liver (NAFL).

Methods

Two radioiodinated probes, [131I]IPBF and [131I]IBF, were developed, and cell uptake studies were used to identify their specific targets for activated macrophages. Biodistribution in normal mice was performed to obtain the pharmacokinetic information of the probes. Apolipoprotein E knockout (ApoE−/−) mice with atherosclerotic aortas were induced by a high-fat and high-cholesterol (HFHC) diet. To investigate the affinity of radiotracers to FR-β, Kd values were determined using in vitro assays. In addition, the assessments of the aorta in the ApoE−/− mice at different stages were performed using in vivo SPECT/CT imaging, and the findings were compared by histology.

Results

Both [131I]IPBF and [131I]IBF were synthesized with > 95% radiochemical purity and up to 3 MBq/nmol molar activity. In vitro assay of [131I]IPBF showed a moderate binding affinity to plasma proteins and specific uptake in activated macrophages. The prolonged blood elimination half-life (t1/2z) of [131I]IPBF (8.14 h) was observed in a pharmacokinetic study of normal mice, which was significantly longer than that of [131I]IBF (t1/2z = 2.95 h). As expected, the Kd values of [131I]IPBF and [131I]IBF in the Raw 264.7 cells were 43.94 ± 9.83 nM and 61.69 ± 15.19 nM, respectively. SPECT imaging with [131I]IPBF showed a high uptake in advanced plaques and NAFL. Radioactivity in excised aortas examined by ex vivo autoradiography further confirmed the specific uptake of [131I]IPBF in high-risk AS plaques.

Conclusions

In summary, we reported a proof-of-concept study of an albumin-binding folate derivative for macrophage imaging. The FR-β-targeted probe, [131I]IPBF, significantly prolongs the plasma elimination half-life and has the potential for the monitoring of AS plaques and concomitant fatty liver.

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Abbreviations

AS:

Atherosclerosis

FR-β:

Folate receptor-β

NAFL:

Non-alcoholic fatty liver

PET:

Positron emission tomography

SPECT:

Single-photon emission computed tomography

CVD:

Cardiovascular disease

HSA:

Human serum albumin

HPLC:

High-performance liquid chromatography

Ox-LDL:

Oxidized-LDL

ORO:

Oil red O

FA:

Folic acid

MWCO:

Molar weight cutoff

WT:

Wild type

HFHC:

High fat and high cholesterol

ApoE−/− :

Apolipoprotein E knockout

SMA:

Smooth muscle actin

%IA/g:

Percentage of injected activity per gram

ROIs:

Regions of interest

H&E:

Hematoxylin-eosin

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Funding

This study was financially supported by the National Natural Science Foundation of China (81901805, 21976150), Major Research Plan of the National Natural Science Foundation of China (91959122), and Joint Fund of the National Natural Science Foundation of China—China National Nuclear Corporation for Nuclear Technology Innovation (U1967222).

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Authors and Affiliations

  1. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, 4221-116 Xiang’An South Rd, Xiamen, 361102, China

    Xuejun Wen, Changrong Shi, Xinying Zeng, Xiaoru Lin, Rongqiang Zhuang, Zhide Guo & Xianzhong Zhang

  2. State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Beijing, Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China

    Liu Yang & Haibo Zhu

  3. Department of Nuclear Medicine & Minnan PET Center, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, 361003, China

    Jinxiong Huang & Yesen Li

Authors
  1. Xuejun Wen
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Contributions

Zhide Guo and Xianzhong Zhang were responsible for the conception and design of the study, the drafting of the manuscript, and the final approval of the version to be published. Xuejun Wen was responsible for the acquisition, analysis and interpretation of the data, and the drafting of the manuscript. Rongqiang Zhuang and Haibo Zhu contributed to critical revision for important intellectual content and final approval of the version to be published. Jinxiong Huang and Yesen Li contributed to the critical revision of the manuscript for important intellectual content and material support. Xiaoru Lin assisted in the synthesis of probes. Changrong Shi, Liu Yang, and Xinying Zeng directed the histopathological characterization of animal models.

Corresponding authors

Correspondence to Zhide Guo or Xianzhong Zhang.

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Ethics approval

Animal experiments were approved by the animal care committee of Xiamen University (ID XMULAC20190157) and carried out in compliance with the national laws related to the conduct of animal experimentation.

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The authors declare no competing interests.

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Wen, X., Shi, C., Yang, L. et al. A radioiodinated FR-β-targeted tracer with improved pharmacokinetics through modification with an albumin binder for imaging of macrophages in AS and NAFL. Eur J Nucl Med Mol Imaging 49, 503–516 (2022). https://doi.org/10.1007/s00259-021-05447-4

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