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Development of an inflammation imaging tracer, 111In-DOTA-DAPTA, targeting chemokine receptor CCR5 and preliminary evaluation in an ApoE−/− atherosclerosis mouse model

  • Original Article
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Journal of Nuclear Cardiology Aims and scope

Abstract

Background

Chemokine receptor 5 (CCR5) plays an important role in atherosclerosis. Our objective was to develop a SPECT tracer targeting CCR5 for imaging plaque inflammation by radiolabeling D-Ala-peptide T-amide (DAPTA), a CCR5 antagonist, with 111In.

Methods

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugated DAPTA (DOTA-DAPTA) was labeled with 111In. Cell uptake studies were conducted in U87-CD4-CCR5 and U87-MG cells. Biodistribution was determined in C57BL/6 mice. Autoradiography, en face and Oil Red O (ORO) imaging studies were performed in ApoE−/− mice.

Results

DOTA-DAPTA was radiolabeled with 111In with high radiochemical purity (> 98%) and specific activity (70 MBq·nmol). 111In-DOTA-DAPTA exhibited fast blood and renal clearance and high spleen uptake. The U87-CD4-CCR5 cells had significantly higher uptake in comparison to the U87-MG cells. The cell uptake was reduced by three times with DAPTA, indicating the receptor specificity of the uptake. Autoradiographic images showed significantly higher lesion uptake of 111In-DOTA-DAPTA in ApoE−/− mice than that in C57BL/6 mice. The tracer uptake in 4 month old ApoE−/− high fat diet (HFD) mice with blocking agent was twofold lower than the same mice without the blocking agent, demonstrating the specificity of the tracer for the CCR5 receptor.

Conclusion

111In-DOTA-DAPTA, specifically targeting chemokine receptor CCR5, is a potential SPECT agent for imaging inflammation in atherosclerosis.

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Abbreviations

CCR5:

Chemokine receptor 5

SPECT:

Single photon emission computed tomography

DAPTA:

d-Ala-peptide T-amide

DOTA:

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

HPLC:

High performance liquid chromatography

ApoE−/− :

Apolipoprotein E knock-out

HFD:

High fat diet

%ID·g:

Percent injected dose per gram

p.i.:

Post injection

ORO:

Oil Red O

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Acknowledgements

This study was funded in part by the Ontario Research Fund (ORF RE07-021). Dr Wei Gan was supported through Mitacs Elevate Postdoctoral Fellowship. We are very grateful for the technical support from Animal Care technicians.

Authorship

Lihui Wei and Terrence Ruddy proposed the study objectives and designed the experiments. Lihui Wei, Wei Gan and Yin Duan performed the chemistry and radiochemistry synthesis and characterization experiments. Julia Petryk and Chantal Gaudet conducted the animal experiments. Lihui Wei and Maryam Kamkar performed the cell uptake studies. Lihui Wei and Terrence Ruddy analyzed the data and drafted the paper. All authors reviewed and provided comments for revising the paper.

Disclosure

Dr. Terrence Ruddy has received research grants from GE HealthCare and Advanced Accelerator Applications. Dr. Lihui Wei is a full-time employee of Nordion Inc. All other authors declare that they have no conflict of interest.

Research Involving Human Participants and/or Animals

The care and use of animals were conducted in compliance with the guidelines of the Canadian Council on Animal Care and with approval from the Animal Care Committee at the University of Ottawa. The procedures performed for this study did not involve human participants.

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Authors and Affiliations

  1. Nordion Inc., 447 March Road, Ottawa, ON, K2K 1X8, Canada

    Lihui Wei PhD

  2. Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, K1Y 4W7, Canada

    Lihui Wei PhD, Julia Petryk, Chantal Gaudet BSc, Maryam Kamkar PhD, Wei Gan PhD, Yin Duan MSc & Terrence D. Ruddy MD

  3. Nordion Lab, Canadian Molecular Imaging Center of Excellence (C-MICE), University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, K1Y 4W7, Canada

    Lihui Wei PhD, Julia Petryk, Wei Gan PhD, Yin Duan MSc & Terrence D. Ruddy MD

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  1. Lihui Wei PhD
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Correspondence to Lihui Wei PhD.

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Wei, L., Petryk, J., Gaudet, C. et al. Development of an inflammation imaging tracer, 111In-DOTA-DAPTA, targeting chemokine receptor CCR5 and preliminary evaluation in an ApoE−/− atherosclerosis mouse model. J. Nucl. Cardiol. 26, 1169–1178 (2019). https://doi.org/10.1007/s12350-018-1203-1

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  • DOI: https://doi.org/10.1007/s12350-018-1203-1

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