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Journal of Nuclear Cardiology

, Volume 24, Issue 2, pp 558–570 | Cite as

A promising carbon-11-labeled sphingosine-1-phosphate receptor 1-specific PET tracer for imaging vascular injury

  • Hongjun Jin
  • Hao Yang
  • Hui Liu
  • Yunxiao Zhang
  • Xiang Zhang
  • Adam J. Rosenberg
  • Yongjian Liu
  • Suzanne E. Lapi
  • Zhude TuEmail author
Original Article

Abstract

Background

Sphingosine-1-phosphate receptor 1 (S1PR1) is highly expressed in vascular smooth muscle cells from intimal lesions. PET imaging using S1PR1 as a biomarker would increase our understanding of its role in vascular pathologies including in-stent restenosis.

Methods

The S1PR1 compound TZ3321 was synthesized for in vitro characterization and labeled with Carbon-11 for in vivo studies. The biodistribution of [11C]TZ3321 was evaluated in normal mice; microPET and immunohistochemistry (IHC) studies were performed using a murine femoral artery wire-injury model of restenosis.

Results

The high potency of TZ3321 for S1PR1 (IC 50 = 2.13 ± 1.63 nM), and high selectivity (>1000 nM) for S1PR1 over S1PR2 and S1PR3 were confirmed. Biodistribution data revealed prolonged retention of [11C]TZ3321 in S1PR1-enriched tissues. MicroPET imaging of [11C]TZ3321 showed higher uptake in the wire-injured arteries of ApoE−/− mice than in injured arteries of wild-type mice (SUV 0.40 ± 0.06 vs 0.28 ± 0.04, n = 6, P < .001); FDG-PET showed no difference (SUV 0.98 ± 0.04 vs 0.94 ± 0.01, n = 6, P > .05). Post-PET autoradiography showed >4-fold higher [11C]TZ3321 retention in the injured artery of ApoE−/− mice than in wild-type mice. Subsequent IHC staining confirmed higher expression of S1PR1 in the neointima of the injured artery of ApoE−/− mice than in wild-type mice.

Conclusions

This preliminary study supports the potential use of PET for quantification of the S1PR1 expression as a biomarker of neointimal hyperplasia.

Keywords

MicroPET imaging inflammation diagnostic and prognostic application biodistribution atherosclerosis 

Abbreviations

ApoE

Apolipoprotein E

AI

Femoral artery wire-injured ApoE-deficient C57BL/6 mice, on high-fat diet

FDG

2-[18F]fluoro-2-deoxy-d-glucose, or [18F]fluorodeoxyglucose

% ID/g

Percent injected dose per gram

NH

Neointimal hyperplasia

ROI

Region of interest

SUV

Standardized uptake value

TAC

Time-activity curve

VSMC

Vascular smooth muscle cell

WtI

Femoral artery wire-injured wild-type C57BL/6 mouse, on normal diet

Notes

Acknowledgments

This work was supported by the DOE-Training in Techniques and Translation grant (DESC0008432) and the Washington University School of Medicine Mallinckrodt Institute of Radiology (MIR) Cyclotron Facility Allotment #14-017. The Carbon-11 used for radiolabeling and the FDG used to conduct this study were provided by the Cyclotron Facility of the Washington University Medical Center. The animal studies presented here were conducted in the MIR Pre-Clinical PET-CT Facility of the Washington University School of Medicine. We thank the staff of the pre-clinical PET-CT facility, the Washington University High Resolution NMR Facility, and the Developmental Biology Histology & Microscopy Core for technical support. We thank Lynne Jones for her assistance in preparation of the manuscript.

Authorship

Conceived and designed the experiments: Hongjun Jin, Hui Liu, and Zhude Tu. Performed the experiments: Hongjun Jin, Yunxiao Zhang, Zhang Xiang, Hao Yang, Hui Liu, and Adam J. Rosenberg. Analyzed the data: Hongjun Jin, Hui Liu, Zhang Xiang, Yongjian Liu, Suzanne E. Lapi, and Zhude Tu. Wrote/revised the paper: Hongjun Jin, Zhang Xiang, Hui Liu, Hao Yang and Zhude Tu.

Disclosure

The authors have indicated that they have no financial conflict of interest.

Research involving human participants and/or animals

All procedures performed in studies involving animals were in accordance with the ethical standards of the institutional research committee, the Washington University School of Medicine Animal Studies Committee. The procedures performed for these studies did not involve human participants.

Supplementary material

12350_2015_391_MOESM1_ESM.doc (356 kb)
Supplementary material 1 (DOC 355 kb)

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Copyright information

© American Society of Nuclear Cardiology 2016

Authors and Affiliations

  • Hongjun Jin
    • 1
  • Hao Yang
    • 1
  • Hui Liu
    • 1
  • Yunxiao Zhang
    • 1
  • Xiang Zhang
    • 1
  • Adam J. Rosenberg
    • 1
  • Yongjian Liu
    • 1
  • Suzanne E. Lapi
    • 1
  • Zhude Tu
    • 1
    Email author
  1. 1.Department of RadiologyWashington University School of MedicineSt. LouisUSA

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