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

Lihui Wei; Julia Petryk; Chantal Gaudet; Maryam Kamkar; Wei Gan; Yin Duan; Terrence D Ruddy

doi:10.1007/s12350-018-1203-1

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. 2019 Aug;26(4):1169-1178. doi: 10.1007/s12350-018-1203-1. Epub 2018 Feb 7.

Authors

Lihui Wei^{1

2

3}, Julia Petryk^{4

5}, Chantal Gaudet⁴, Maryam Kamkar⁴, Wei Gan^{4

5}, Yin Duan^{4

5}, Terrence D Ruddy^{4

5}

Affiliations

¹ Nordion Inc., 447 March Road, Ottawa, ON, K2K 1X8, Canada. [email protected].
² Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, K1Y 4W7, Canada. [email protected].
³ Nordion Lab, Canadian Molecular Imaging Center of Excellence (C-MICE), University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, K1Y 4W7, Canada. [email protected].
⁴ Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, K1Y 4W7, Canada.
⁵ Nordion Lab, Canadian Molecular Imaging Center of Excellence (C-MICE), University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, K1Y 4W7, Canada.

PMID: 29417414
DOI: 10.1007/s12350-018-1203-1

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.

Keywords: 111In-DOTA-DAPTA; ApoE−/− mice; CCR5; atherosclerosis; autoradiography.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alanine / chemistry*
Animals
Atherosclerosis / diagnostic imaging
CD4-Positive T-Lymphocytes / cytology
Cell Line, Tumor
Female
Heterocyclic Compounds, 1-Ring / chemistry*
Humans
Indium Radioisotopes / chemistry*
Inflammation
Mice
Mice, Inbred C57BL
Mice, Knockout, ApoE
Receptors, CCR5 / chemistry*
Tomography, Emission-Computed, Single-Photon

Substances

CCR5 protein, human
CCR5 protein, mouse
D-Ala-peptide T-amide
Heterocyclic Compounds, 1-Ring
Indium Radioisotopes
Receptors, CCR5
1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
Alanine