Molecular imaging of cancer with copper-64 radiopharmaceuticals and positron emission tomography (PET)

Abstract

Molecular imaging has evolved over the past several years into an important tool for diagnosing, understanding, and monitoring disease. Molecular imaging has distinguished itself as an interdisciplinary field, with contributions from chemistry, biology, physics, and medicine. The cross-disciplinary impetus has led to significant achievements, such as the development of more sensitive imaging instruments and robust, safer radiopharmaceuticals, thereby providing more choices to fit personalized medical needs. Molecular imaging is making steadfast progress in the field of cancer research among others. Cancer is a challenging disease, characterized by heterogeneity, uncontrolled cell division, and the ability of cancer cells to invade other tissues. Researchers are addressing these challenges by aggressively identifying and studying key cancer-specific biomarkers such as growth factor receptors, protein kinases, cell adhesion molecules, and proteases, as well as cancer-related biological processes such as hypoxia, apoptosis, and angiogenesis. Positron emission tomography (PET) is widely used by clinicians in the United States as a diagnostic molecular imaging tool. Small-animal PET systems that can image rodents and generate reconstructed images in a noninvasive manner (with a resolution as low as 1 mm) have been developed and are used frequently, facilitating radiopharmaceutical development and drug discovery. Currently, [(18)F]-labeled 2-fluorodeoxyglucose (FDG) is the only PET radiotracer used for routine clinical evaluation (primarily for oncological imaging). There is now increasing interest in nontraditional positron-emitting radionuclides, particularly those of the transition metals, for imaging with PET because of increased production and availability. Copper-based radionuclides are currently being extensively evaluated because they offer a varying range of half-lives and positron energies. For example, the half-life (12.7 h) and decay properties (beta(+), 0.653 MeV, 17.8%; beta(-), 0.579 MeV, 38.4 %; the remainder is electron capture) of (64)Cu make it an ideal radioisotope for PET imaging and radiotherapy. In addition, the well-established coordination chemistry of copper allows for its reaction with a wide variety of chelator systems that can potentially be linked to antibodies, proteins, peptides, and other biologically relevant molecules. New chelators with greater in vivo stability, such as the cross-bridged (CB) versions of tetraazamacrocyclic 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), are now available. Finally, one of the major aspects of successful imaging is the identification and characterization of a relevant disease biomarker at the cellular and subcellular level and the ensuing development of a highly specific targeting moiety. In this Account, we discuss specific examples of PET imaging with new and improved (64)Cu-based radiopharmaceuticals, highlighting the study of some of the key cancer biomarkers, such as epidermal growth-factor receptor (EGFR), somatostatin receptors (SSRs), and integrin alpha(v)beta(3).

Figure 1

Schematic of imaging with positron emission tomography (PET). The positron travels away from its origin and then collides with a negatively charged electron in tissue, producing annihilation radiation of two 511 keV photons approximately 180 degrees apart. These coincident emissions are detected by the PET scanner.

Figure 2

Macrocyclic chelators that have been investigated for chelating copper radionuclides.

Figure 3

Biodistribution data of selected ⁶⁴Cu-labeled cyclam and bridged cyclam analogs at 24 h p.i. (post-injection) in normal rats. Adapted from references.,,

Figure 4

Schematic of a tumor cell showing the various intracellular, cell surface and extracellular targets available for molecular imaging.

Figure 5

Somatostatin analogs that have been conjugated with various metal chelators and labeled with ¹¹¹In or ⁶⁴Cu for evaluating somatostatin receptor positive tumors in rodent models and humans.

Figure 6

(A) Projection microPET images of A431 tumor- bearing nude mice after 20 and 46 hours post-administration 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 microPET 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) MicroPET/computed tomography co-registration 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 .

Figure 7

Small-animal PET/CT of PTH-treated mice. Calvarium uptake of ⁶⁴Cu-CB-TE2A-c(RGDyK) was higher in PTH-treated mice (7.4 MBq [199 μCi],115 ng, SUV = 0.53) than in control mice (7.7 MBq [209 μCi], 121 ng, SUV = 0.22) (A). In PTH-treated mice, uptake was reduced in all tissues, including calvarium, after injection of c(RGDyK) (PTH [left]: 159 μCi, 84 ng, SUV = 0.33; block [right]: 164 μCi, 87 ng, SUV = 0.18) (B). Arrowheads indicate calvarium of each animal. Fiducials (*) are indicated. Reprinted by permission of the Society of Nuclear Medicine from Reference .