Theranostic Nuclear Medicine with Gallium-68, Lutetium-177, Copper-64/67, Actinium-225, and Lead-212/203 Radionuclides

Abstract

Molecular changes in malignant tissue can lead to an increase in the expression levels of various proteins or receptors that can be used to target the disease. In oncology, diagnostic imaging and radiotherapy of tumors is possible by attaching an appropriate radionuclide to molecules that selectively bind to these target proteins. The term “theranostics” describes the use of a diagnostic tool to predict the efficacy of a therapeutic option. Molecules radiolabeled with γ-emitting or β+-emitting radionuclides can be used for diagnostic imaging using single photon emission computed tomography or positron emission tomography. Radionuclide therapy of disease sites is possible with either α-, β-, or Auger-emitting radionuclides that induce irreversible damage to DNA. This Focus Review centers on the chemistry of theranostic approaches using metal radionuclides for imaging and therapy. The use of tracers that contain β+-emitting gallium-68 and β-emitting lutetium-177 will be discussed in the context of agents in clinical use for the diagnostic imaging and therapy of neuroendocrine tumors and prostate cancer. A particular emphasis is then placed on the chemistry involved in the development of theranostic approaches that use copper-64 for imaging and copper-67 for therapy with functionalized sarcophagine cage amine ligands. Targeted therapy with radionuclides that emit α particles has potential to be of particular use in late-stage disease where there are limited options, and the role of actinium-225 and lead-212 in this area is also discussed. Finally, we highlight the challenges that impede further adoption of radiotheranostic concepts while highlighting exciting opportunities and prospects.

Recent Progress in Peptide-Based Molecular Probes for Disease Bioimaging

“…First, the spatial resolution of current radioactive imaging is relatively low when compared to MRI . Second, the usage of radioactive isotopes, especially those with a long half-life, could potentially harm the subjects and cause issues in waste storage and processing, but there are also difficulties associated with the generation, synthesis, and purification of the radioactive isotopes with a short half-life . To facilitate the purification of radioactive isotopes, an organic-matrix based 68 Ge/ 68 Ga generator has been developed, allowing the eluent to be directly used for labeling without further purification .…”

Diagnostic Positron Emission Tomography Imaging with Zirconium-89 Desferrioxamine B Squaramide: From Bench to Bedside

“…Some metastatic prostate cancers overexpress prostate-specific membrane antigen (PSMA), an excellent target for both diagnostic imaging and radionuclide therapy . Low molecular-weight inhibitors of PSMA based on a lysine-ureido-glutamate pharmacophore bind to PSMA with high avidity and selectivity and have been utilized in both PET imaging and therapeutic agents. ,− To synthesize a zirconium-89 PSMA imaging agent, we prepared bivalent [ 89 Zr]ZrDFOSq–BisPhPSMA (Figure ). Mice bearing LNCaP tumors were administered [ 89 Zr]ZrDFOSq–BisPhPSMA (∼2 MBq) and PET images were acquired at 1, 2, 4, and 18 h postinjection.…”

“…Peptide-based and small molecule targeted PET imaging agents that are in common clinical use are normally radiolabeled with either fluorine-18, gallium-68, or copper-64 . The radioactive half-lives of these radionuclides have advantages with respect to radiation exposure but do impose certain restrictions on imaging time points.…”

Tumor targeted alpha particle therapy with an actinium-225 labelled antibody for carbonic anhydrase IX

“…The potential for radionuclide therapy is highlighted by the recent clinical approval of two radiopharmaceuticals based on β − emitting lutetium-177, [ 177 Lu]Lu(DOTATATE) and [ 177 Lu]Lu(PSMA-617), for the treatment of somatostatin receptor-positive neuroendocrine tumors and metastatic castrate-resistant prostate cancer, respectively. 1–11…”

“…13 Actinium-225 has a radioactive half-life of 9.9 days and decays to bismuth-209 ( t 1/2 = 1.9 × 10 19 years) via the release of a total of four α particles (Eα 2+ = 5.9–8.4 MeV) and two β − particles. 11,16…”