Copper-64 radiopharmaceuticals for PET imaging of cancer: advances in preclinical and clinical research

Abstract

Copper-64 (T(1/2) = 12.7 hours; beta(+), 0.653 MeV [17.8 %]; beta(-), 0.579 MeV [38.4 %]) has decay characteristics that allow for positron emission tomography (PET) imaging and targeted radiotherapy of cancer. The well-established coordination chemistry of copper allows for its reaction with a wide variety of chelator systems that can potentially be linked to peptides and other biologically relevant small molecules, antibodies, proteins, and nanoparticles. The 12.7-hours half-life of 64Cu provides the flexibility to image both smaller molecules and larger, slower clearing proteins and nanoparticles. In a practical sense, the radionuclide or the 64Cu-radiopharmaceuticals can be easily shipped for PET imaging studies at sites remote to the production facility. Due to the versatility of 64Cu, there has been an abundance of novel research in this area over the past 20 years, primarily in the area of PET imaging, but also for the targeted radiotherapy of cancer. The biologic activity of the hypoxia imaging agent, 60/64Cu-ATSM, has been described in great detail in animal models and in clinical PET studies. An investigational new drug application for 64Cu-ATSM was recently approved by the U.S. Food and Drug Administration (FDA) in the United States, paving the way for a multicenter trial to validate the utility of this agent, with the hopeful result being FDA approval for routine clinical use. This article discusses state-of-the-art cancer imaging with 64Cu radiopharmaceuticals, including 64Cu-ATSM for imaging hypoxia, 64Cu-labeled peptides for tumor-receptor targeting, (64)Cu-labeled monoclonal antibodies for targeting tumor antigens, and 64Cu-labeled nanoparticles for cancer targeting. The emphasis of this article will be on the new scientific discoveries involving (64)Cu radiopharmaceuticals, as well as the translation of these into human studies.

FIG. 1.

Structures of macrocyclic chelators for complexing copper radionuclides.

FIG. 2.

Transaxial positron emission tomography/computed tomography (PET/CT) images showing the CT image (top left), [¹⁸F]-FDG (Fluorine-18-2-fluoro-2-deoxy-d-glucose) image, ⁶⁰Cu-ATSM and ⁶⁴Cu-ATSM images recorded between 30 and 60 minutes in 2 patients with known cervical cancers. (A) Images recorded for a patient who responded to conventional radiotherapy and (B) images from a nonresponder. Reprinted by permission of the Society of Nuclear Medicine from reference .

FIG. 3.

Amino-acid sequences of somatostatin analogs used in imaging with ⁶⁴Cu and the chelators used to complex ⁶⁴Cu.

FIG. 4.

Structures of c(RGDxK) peptides and proteins used in the imaging of α_vβ₃ expression in tumor angiogenesis and osteoclasts. x, d-Tyr or d-Phe.

FIG. 5.

(A) Projection micro-PET (positron emission tomography) images of A431 tumor-bearing nude mice after 20 and 46 hours postadministration of ⁶⁴Cu-DOTA-cetuximab, with and without an injected blocking dose 20 hours prior to the imaging dose (5.6 MBq, 6 g, left; 5.6 MBq, 1 mg of cetuximab, right). (B) Coronal micro-PET images of ⁶⁴Cu-DOTA-cetuximab in A431 [epidermal growth factor receptor (EGFR)-positive] and MDA-MB-435 (EGFR-negative) tumor-bearing mice after 19 and 48 hours postadministration of ⁶⁴Cu-DOTA-cetuximab. (C) micro-PET/computed tomography coregistration images of ⁶⁴Cu-DOTA-cetuximab in a mouse bearing both A431 and MDA-MB-435 tumors (arrow) at 24 hours postinjection. Reprinted by permission of the Mary Ann Liebert, Inc., publishers from reference .

FIG. 6.

Structures of nanoparticles used in imaging include DOTA-conjugated quantum dots, DOTA- and RGD peptide-conjugated single-walled carbon nanotube nanoparticles, PEGylated DOTA star copolymers, and PEGylated DOTA-shell cross-lined (SCK) nanoparticles.