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64Cu PET Imaging of the CXCR4 Chemokine Receptor Using a Cross-Bridged Cyclam Bis-Tetraazamacrocyclic Antagonist

Burke, Benjamin P.; Miranda, Cecilia; Lee, Rhiannon; Renard, Isaline; Nigam, Shubhanchi; Clemente, Goncalo; D'Huys, Thomas; Ruest, Torsten; Domarkas, Juozas; Thompson, James; Hubin, Timothy; Schols, Dominique; Cawthorne, Chris; Archibald, Stephen J.


Benjamin P. Burke

Cecilia Miranda

Rhiannon Lee

Isaline Renard

Shubhanchi Nigam

Goncalo Clemente

Thomas D'Huys

Torsten Ruest

Juozas Domarkas

James Thompson

Timothy Hubin

Dominique Schols

Chris Cawthorne


© 2020 by the Society of Nuclear Medicine and Molecular Imaging. Expression of the chemokine receptor chemokine C-X-C motif receptor 4 (CXCR4) plays an important role in cancer metastasis, in autoimmune diseases, and during stem cell-based repair processes after stroke and myocardial infarction. Previously reported PET imaging agents targeting CXCR4 suffer from either high nonspecific uptake or bind only to the human form of the receptor. The objective of this study was to develop a high-stability 64Cu-labeled small-molecule PET agent for imaging both human and murine CXCR4 chemokine receptors. Methods: Synthesis, radiochemistry, stability and radioligand binding assays were performed for the novel tracer 64Cu-CuCB-bicyclam. In vivo dynamic PET studies were performed on mice bearing U87 (CXCR4 low-expressing) and U87.CXCR4 (human-CXCR4 high-expressing) tumors. Biodistribution and receptor blocking studies were performed on CD1-IGS immunocompetent mice. CXCR4 expression on tumor and liver disaggregates was confirmed using a combination of immunohistochemistry, quantitative polymerase chain reaction, and Western blot. Results:64Cu-CuCB-bicyclam has a high affinity for both the human and the murine variants of the CXCR4 receptor (half-maximal inhibitory concentration, 8 nM [human]/2 nM [murine]) and can be obtained from the parent chelator that has low affinity. In vitro and in vivo studies demonstrate specific uptake in CXCR4-expressing cells that can be blocked by more than 90% using a higher-affinity antagonist, with limited uptake in non-CXCR4-expressing organs and high in vivo stability. The tracer was also able to selectively displace the CXCR4 antagonists AMD3100 and AMD3465 from the liver. Conclusion: The tetraazamacrocyclic small molecule 64Cu-CuCB-bicyclam has been shown to be an imaging agent for the CXCR4 receptor that is likely to be applicable across a range of species. It has high affinity and stability and is suitable for preclinical research in immunocompetent murine models.


Burke, B. P., Miranda, C., Lee, R., Renard, I., Nigam, S., Clemente, G., …Archibald, S. J. (2020). 64Cu PET Imaging of the CXCR4 Chemokine Receptor Using a Cross-Bridged Cyclam Bis-Tetraazamacrocyclic Antagonist. Journal of nuclear medicine, 61(1), 123-128.

Journal Article Type Article
Acceptance Date Jun 3, 2019
Online Publication Date Jun 14, 2019
Publication Date Jan 1, 2020
Deposit Date Aug 7, 2019
Publicly Available Date Jun 15, 2020
Journal Journal of Nuclear Medicine
Print ISSN 0161-5505
Electronic ISSN 2159-662X
Publisher Society of Nuclear Medicine
Peer Reviewed Peer Reviewed
Volume 61
Issue 1
Pages 123-128
Keywords Radiology Nuclear Medicine and imaging
Public URL
Publisher URL


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