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Noninvasive Imaging of Osteoclasts in Parathyroid Hormone–Induced Osteolysis Using a ⁶⁴Cu-Labeled RGD Peptide

¹ Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri; ² Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri; and ³ Department of Medicine, Washington University School of Medicine, St. Louis, Missouri

Correspondence: For correspondence or reprints contact: Carolyn J. Anderson, PhD, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd., Campus Box 8225, St. Louis, MO 63110. E-mail: andersoncj{at}wustl.edu

Bone diseases are often a result of increased numbers of osteoclasts, or bone-resorbing cells. Bone metastases are a significant cause of morbidity in many types of cancer. An imaging agent targeting osteoclasts, which are upregulated in osteolytic lesions, may facilitate earlier follow-up in patients with osteolytic or mixed bone metastases. Osteoclasts express high levels of _vß₃ integrin, to which peptides containing the Arg-Gly-Asp (RGD) sequence are known to bind. We proposed that radiolabeled RGD peptides could be used to detect osteoclasts in lytic bone lesions. Methods: The cross-bridged macrocyclic chelator 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A) was conjugated to c(RGDyK) for radiolabeling with ⁶⁴Cu (t_1/2, 12.7 h; ß⁺, 17.4%; E_ß+max, 656 keV; ß^–, 39%; E_ß–max, 573 keV). The in vitro affinity of Cu(II)-CB-TE2A-c(RGDyK) for _vß₃ and _vß₅ was evaluated in a heterologous competitive binding assay. Ex vivo uptake was examined in osteoclasts prepared from bone marrow macrophages. As a proof of principle, biodistribution and imaging studies were performed on parathyroid hormone (PTH)–induced osteolysis in the calvarium. Results: Cu-CB-TE2A-c(RGDyK) was shown to have a 30-fold higher affinity for _vß₃ than for _vß_5. Osteoclasts were shown to specifically take up ⁶⁴Cu-CB-TE2A-c(RGDyK). However, bone marrow macrophages showed only nonspecific uptake. PTH treatment increased calvarial uptake of ⁶⁴Cu-CB-TE2A-c(RGDyK), compared with uptake in mice receiving a sham treatment. In addition, calvarial uptake correlated linearly with the number of osteoclasts on the bone surface. Conclusion: These results suggest that ⁶⁴Cu-CB-TE2A-c(RGDyK) selectively binds _vß₃ on osteoclasts and may potentially be used to identify increased numbers of osteoclasts in osteolytic bone diseases such as osteolytic bone metastasis and inflammatory osteolysis.

Key Words: bone • PET/CT • radiopharmaceuticals • copper-64 • integrin • osteoclast

COPYRIGHT © 2007 by the Society of Nuclear Medicine, Inc.

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