Copper-64 Radiopharmaceuticals for PET Imaging of Cancer: Advances in Preclinical and Clinical Research

Abstract

Summation Copper-64 (T1/2=12.7 hours; β+, 0.653MeV [17.8 %]; β−, 0.579MeV [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, 64Cu-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 64Cu radiopharmaceuticals, as well as the translation of these into human studies.

Noninvasive positron emission tomography and fluorescence imaging of CD133 + tumor stem cells

“…S3A). Particularly remarkable was the much higher tracer uptake liver [an organ exhibiting relatively high unspecific activity because of high blood perfusion, antibody metabolism, and potential transchelation of 64 Cu (28,36)]. The tumor-to-contralateral background, tumor-to-blood pool, and tumor-to-liver contrasts were 21.4 ± 8.2, 2.7 ± 0.9, and 2.6 ± 0.8 at 24 h and 32.8 ± 19, 6.4 ± 2.5, and 5.4 ± 1.8 at 48 h p.i., respectively.…”

“…PET is highly sensitive and is widely used for clinical whole-body diagnostic imaging. As a PET nuclide, we used 64 Cu (t 1/2 = 12.7 h), which allows long-term tracking for at least 48 h, to follow the tumoral accumulation of relatively large molecules such as antibodies, that exhibit relatively slow tumor penetration (28). We chose S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA, hereafter abbreviated as NOTA) as the 64 Cu chelator, because high labeling efficiencies and high in vivo stability have been reported for 64 Cu-NOTA-antibody conjugates (29).…”

Stem Cell Monitoring with a Direct or Indirect Labeling Method

“…To track the transplanted stem cells, first, the direct-labeled stem cells are transplanted to the target tissue/ organ. Then, noninvasive imaging including MRI or radionuclide imaging using PET or SPECT is performed at the target site for detection of transplanted stem cells [14,45]. 64 Cu can react with a wide variety of chelator systems including 1,4,7,10-tetraazacyclododecane-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane-1,4,7-triacetic acid because of its wellestablished coordination chemistry [46,47].…”

Positive Progress in ImmunoPET—Not Just a Coincidence

“…In the liver, transchelation of radionuclides such as 64 Cu to the metal-binding proteins superoxide dismutase and metallothionein precludes imaging of hepatic disease with radiometals. 8 …”