Search Results (30)

Background: While gallium-68 has traditionally dominated PET imaging in oncology, copper radionuclides have sparked interest for their potential applications in nuclear medicine and theranostics. Considering the advantageous physical decay properties of copper-61 compared to those of gallium-68, we describe a fully automated GMP-compliant synthesis process for ⁶¹Cu-based radiopharmaceuticals and demonstrate their in vivo application for targeting the overexpressed PSMA by PET/MR imaging. Methods: Copper-61 was obtained through the irradiation of natural zinc liquid targets in a biomedical cyclotron. [⁶¹Cu]Cu-DOTAGA-PSMA-I&T and [⁶¹Cu]Cu-NODAGA-PSMA-I&T were produced without manual intervention in two Synthera^® Extension modules. Radiochemical purity was analyzed by radio-HPLC and iTLC. Cellular uptake was evaluated in LNCaP and DU145 cells. In vivo PET/MRI was performed in control mice to evaluate the biodistribution of both radiopharmaceuticals, and in tumor-bearing mice to assess the targeting ability towards PSMA. Results: The fully automated process developed proved to be effective for the synthesis of ⁶¹Cu-based radiopharmaceuticals, with appropriate molar activities. The final products exhibited high radiochemical purity (>98%) and remained stable for up to 6 h after the EOS. A time-dependent increase in cellular uptake was observed in LNCaP cells, but not in DU145 cells. As opposed to [⁶¹Cu]Cu-NODAGA-PSMA-I&T, [⁶¹Cu]Cu-DOTAGA-PSMA-I&T exhibited poor kinetic stability in vivo. Subsequent PET/MR imaging with [⁶¹Cu]Cu-NODAGA-PSMA-I&T showed tumor uptake lasting up to 4 h post-injection, predominant renal clearance, and no detectable accumulation in non-targeted organs. Conclusions: These results demonstrate the feasibility of the implemented process, which yields adequate amounts of high-quality radiopharmaceuticals and can be adapted to any standard production facility. This streamlined approach enhances reproducibility and scalability, bringing copper-61 closer to widespread clinical use, to the detriment of the conventionally accepted gallium-68. Full article

Background: Fibroblast activation protein (FAP)-targeted theranostic radiopharmaceuticals have shown desired tumor-to-background organ selectivity due to the ubiquitous presence of FAP within the tumor microenvironment. However, suboptimal tumor retention and fast clearance have hindered their use to deliver effective cancer therapies. With well-documented FAP-targeting moieties and linkers appending them to optimal chelators, the development of copper radiopharmaceuticals has attracted considerable interest, given the fact that an ideal theranostic pair of copper radionuclides (⁶⁴Cu: t_1/2 = 12.7 h; 17.4% β⁺; E_β⁺_max = 653 keV and ⁶⁷Cu: t_1/2 = 2.58 d; 100% β⁻; E_β⁻_max = 562 keV) are available. Herein, we report our design, synthesis, and comparative evaluation of monovalent and divalent FAP-targeted theranostic conjugates constructed from our previously reported bifunctional chelator scaffold (BFS) based on 1,4,8,11-tetraaza-bicyclo [6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A), which forms the most stable complex with Cu(II). Methods: After synthesis and characterization, the monovalent and divalent conjugates were radiolabeled with ⁶⁴Cu for in vitro cell assays, followed by in vivo positron emission tomography (PET) imaging evaluation in relevant mouse models. Results: Both ⁶⁴Cu-labeled conjugates showed high in vitro stability and anticipated FAP-mediated cell binding and internalization. The divalent one showed significantly higher FAP-specific tumor uptake than its monovalent counterpart. Conclusions: Our results demonstrate that the BFS-based multivalent approach can be practically used to generate FAP-targeted radiotheranostic agents for effective cancer diagnosis and treatment. Full article

⁶⁴Cu is gaining recognition not only for its diagnostic capabilities in nuclear medical imaging but also for its therapeutic and theranostic potential. The simultaneous βˉ and Auger emissions of ⁶⁴Cu can be utilized to induce a therapeutic effect on cancerous lesions. The finding of the exceptional biodistribution characteristics of the radionuclide ⁶⁴Cu, when administered as basic copper ions, has highlighted its potential therapeutic application in cancer treatment. Preclinical and clinical research on the effectiveness of [⁶⁴Cu]CuCl₂ as a theranostic radiopharmaceutical has commenced only in the past decade. Current clinical studies are increasingly demonstrating the high specificity and uptake of [⁶⁴Cu]Cu²⁺ by malignant tissues during early cancer progression, indicating its potential for early cancer diagnosis across various organs. This short review aims to present the latest preclinical studies involving [⁶⁴Cu]CuCl₂, offering valuable insights for researchers planning new in vitro and in vivo studies to explore the theranostic potential of [⁶⁴Cu]Cu²⁺. Full article

Copper (Cu) is a critical element for cancer cell proliferation and considerably accumulates in the nucleus. ⁶⁴Cu²⁺ is an anticancer radiopharmaceutical that targets the copper requirement of cancer cells. However, intravenously injected ⁶⁴Cu²⁺ ions primarily accumulate in the liver. Ligand complexation of ⁶⁴Cu²⁺ may be a promising method for increasing tumor delivery by reducing liver uptake. In this study, we used three tripodal amine ligands [tris(2-aminoethyl)amine (Tren), diethylenetriamine (Dien), and tris(2-pyridylmethyl)amine (TPMA)] to enclose ⁶⁴Cu²⁺ ions and compared their in vivo tumor and liver uptakes using a tumor-bearing xenograft mouse model of the extrahepatic bile duct carcinoma cell line TFK-1. We examined intracellular Cu distribution using microparticle-induced X-ray emission (micro-PIXE) analysis of these compounds. ⁶⁴Cu²⁺-Tren and ⁶⁴Cu²⁺-Dien showed higher tumor uptake than ⁶⁴Cu²⁺-TPMA and ⁶⁴Cu²⁺ ions in TFK-1 tumors. Among the three ⁶⁴Cu²⁺ complexes and ⁶⁴Cu²⁺ ions, liver uptake was inversely correlated with tumor uptake. Micro-PIXE analysis showed that in vitro cellular uptake was similar to in vivo tumor uptake, and nuclear delivery was the highest for ⁶⁴Cu²⁺-Tren. Conclusively, an inverse correlation between tumor and liver uptake was observed using three ⁶⁴Cu²⁺ complexes of tripodal amine ligands and ⁶⁴Cu²⁺ ions. These results provide useful information for the future development of anticancer ⁶⁴Cu radiopharmaceuticals. Full article

Cancer theragnostics is a novel approach that combines diagnostic imaging and radionuclide therapy. It is based on the use of a pair of radiopharmaceuticals, one optimized for positron emission tomography imaging through linkage to a proper radionuclide, and the other bearing an alpha- or beta-emitter isotope that can induce significant damage to cancer cells. In recent years, the use of theragnostics in nuclear medicine clinical practice has increased considerably, and thus investigation has focused on the identification of novel radionuclides that can bind to molecular targets that are typically dysregulated in different cancers. The major advantages of the theragnostic approach include the elimination of multi-step procedures, reduced adverse effects to normal tissues, early diagnosis, better predictive responses, and personalized patient care. This review aims to discuss emerging theragnostic molecules that have been investigated in a series of human malignancies, including gliomas, thyroid cancer, neuroendocrine tumors, cholangiocarcinoma, and prostate cancer, as well as potent and recently introduced molecular targets, like cell-surface receptors, kinases, and cell adhesion proteins. Furthermore, special reference has been made to copper radionuclides as theragnostic agents and their radiopharmaceutical applications since they present promising alternatives to the well-studied gallium-68 and lutetium-177. Full article

Angiogenesis plays a crucial role in tumour progression and metastatic spread; therefore, the development of specific vectors targeting angiogenesis has attracted the attention of several researchers. Since angiogenesis-associated aminopeptidase N (APN/CD13) is highly expressed on the surface of activated endothelial cells of new blood vessels and a wide range of tumour cells, it holds great promise for imaging and therapy in the field of cancer medicine. The selective binding capability of asparagine-glycine-arginine (NGR) motif containing molecules to APN/CD13 makes radiolabelled NGR peptides promising radiopharmaceuticals for the non-invasive, real-time imaging of APN/CD13 overexpressing malignancies at the molecular level. Preclinical small animal model systems are major keystones for the evaluation of the in vivo imaging behaviour of radiolabelled NGR derivatives. Based on existing literature data, several positron emission tomography (PET) and single-photon emission computed tomography (SPECT) radioisotopes have been applied so far for the labelling of tumour vasculature homing NGR sequences such as Gallium-68 (⁶⁸Ga), Copper-64 (⁶⁴Cu), Technetium-99m (^99mTc), Lutetium-177 (¹⁷⁷Lu), Rhenium-188 (¹⁸⁸Re), or Bismuth-213 (²¹³Bi). Herein, a comprehensive overview is provided of the recent preclinical experiences with radiolabelled imaging probes targeting angiogenesis. Full article

Antibody and nanobody-based copper-64 radiopharmaceuticals are increasingly being proposed as theranostic tools in multiple human diseases. While the production of copper-64 using solid targets has been established for many years, its use is limited due to the complexity of solid target systems, which are available in only a few cyclotrons worldwide. In contrast, liquid targets, available in virtually in all cyclotrons, constitute a practical and reliable alternative. In this study, we discuss the production, purification, and radiolabeling of antibodies and nanobodies using copper-64 obtained from both solid and liquid targets. Copper-64 production from solid targets was performed on a TR-19 cyclotron with an energy of 11.7 MeV, while liquid target production was obtained by bombarding a nickel-64 solution using an IBA Cyclone Kiube cyclotron with 16.9 MeV on target. Copper-64 was purified from both solid and liquid targets and used to radiolabel NODAGA-Nb, NOTA-Nb, and DOTA-Trastuzumab conjugates. Stability studies were conducted on all radioimmunoconjugates in mouse serum, PBS, and DTPA. Irradiation of the solid target yielded 13.5 ± 0.5 GBq with a beam current of 25 ± 1.2 μA and an irradiation time of 6 h. On the other hand, irradiation of the liquid target resulted in 2.8 ± 1.3 GBq at the end of bombardment (EOB) with a beam current of 54.5 ± 7.8 μA and an irradiation time of 4.1 ± 1.3 h. Successful radiolabeling of NODAGA-Nb, NOTA-Nb, and DOTA-Trastuzumab with copper-64 from both solid and liquid targets was achieved. Specific activities (SA) obtained with the solid target were 0.11, 0.19, and 0.33 MBq/μg for NODAGA-Nb, NOTA-Nb, and DOTA-trastuzumab, respectively. For the liquid target, the corresponding SA values were 0.15, 0.12, and 0.30 MBq/μg. Furthermore, all three radiopharmaceuticals demonstrated stability under the testing conditions. While solid targets have the potential to produce significantly higher activity in a single run, the liquid process offers advantages such as speed, ease of automation, and the feasibility of back-to-back production using a medical cyclotron. In this study, successful radiolabeling of antibodies and nanobodies was achieved using both solid and liquid targets approaches. The radiolabeled compounds exhibited high radiochemical purity and specific activity, rendering them suitable for subsequent in vivo pre-clinical imaging studies. Full article

Copper-64 (T_1/2 = 12.7 h) is a positron and beta-emitting isotope, with decay characteristics suitable for both positron emission tomography (PET) imaging and radiotherapy of cancer. Copper-67 (T_1/2 = 61.8 h) is a beta and gamma emitter, appropriate for radiotherapy β-energy and with a half-life suitable for single-photon emission computed tomography (SPECT) imaging. The chemical identities of ⁶⁴Cu and ⁶⁷Cu isotopes allow for convenient use of the same chelating molecules for sequential PET imaging and radiotherapy. A recent breakthrough in ⁶⁷Cu production opened previously unavailable opportunities for a reliable source of ⁶⁷Cu with high specific activity and purity. These new opportunities have reignited interest in the use of copper-containing radiopharmaceuticals for the therapy, diagnosis, and theranostics of various diseases. Herein, we summarize recent (2018–2023) advances in the use of copper-based radiopharmaceuticals for PET, SPECT imaging, radiotherapy, and radioimmunotherapy. Full article

Angiogenesis-related cell-surface molecules, including integrins, aminopeptidase N, vascular endothelial growth factor, and gastrin-releasing peptide receptor (GRPR), play a crucial role in tumour formation. Radiolabelled imaging probes targeting angiogenic biomarkers serve as valuable vectors in tumour identification. Nowadays, there is a growing interest in novel radionuclides other than gallium-68 (⁶⁸Ga) or copper-64 (⁶⁴Cu) to establish selective radiotracers for the imaging of tumour-associated neo-angiogenesis. Given its ideal decay characteristics (E_β⁺_average: 632 KeV) and a half-life (T_1/2 = 3.97 h) that is well matched to the pharmacokinetic profile of small molecules targeting angiogenesis, scandium-44 (⁴⁴Sc) has gained meaningful attention as a promising radiometal for positron emission tomography (PET) imaging. More recently, intensive research has been centered around the investigation of ⁴⁴Sc-labelled angiogenesis-directed radiopharmaceuticals. Previous studies dealt with the evaluation of ⁴⁴Sc-appended a_vb₃ integrin–affine Arg-Gly-Asp (RGD) tripeptides, GRPR-selective aminobenzoyl–bombesin analogue (AMBA), and hypoxia-associated nitroimidazole derivatives in the identification of various cancers using experimental tumour models. Given the tumour-related hypoxia- and angiogenesis-targeting capability of these PET probes, ⁴⁴Sc seems to be a strong competitor of the currently used positron emitters in radiotracer development. In this review, we summarize the preliminary preclinical achievements with ⁴⁴Sc-labelled angiogenesis-specific molecular probes. Full article

Theranostic matched pairs of radionuclides have aroused interest during the last couple of years, and in that sense, copper is one element that has a lot to offer, and although ⁶¹Cu and ⁶⁴Cu are slowly being established as diagnostic radionuclides for PET, the availability of the therapeutic counterpart ⁶⁷Cu plays a key role for further radiopharmaceutical development in the future. Until now, the ⁶⁷Cu shortage has not been solved; however, different production routes are being explored. This project aims at the production of no-carrier-added ⁶⁷Cu with high radionuclidic purity with a medical 30MeV compact cyclotron via the ⁷⁰Zn(p,α)⁶⁷Cu reaction. With this purpose, proton irradiation of electrodeposited ⁷⁰Zn targets was performed followed by two-step radiochemical separation based on solid-phase extraction. Activities of up to 600MBq ⁶⁷Cu at end of bombardment, with radionuclidic purities over 99.5% and apparent molar activities of up to 80MBq/nmol, were quantified. Full article

Copper is required for cancer cell proliferation and tumor angiogenesis. Copper-64 radionuclide (⁶⁴Cu), a form of copper chloride (⁶⁴CuCl₂), is rapidly emerging as a diagnostic PET/CT tracer in oncology. It may also represent an interesting alternative to gallium-68 (⁶⁸Ga) as a radionuclide precursor for labelling radiopharmaceuticals used to investigate neuroendocrine tumors and prostate cancer. This emerging interest is also related to the nuclear properties of ⁶⁴CuCl₂ that make it an ideal theragnostic nuclide. Indeed, ⁶⁴CuCl₂ emits β⁺ and β^- particles together with high-linear-energy-transfer Auger electrons, suggesting the therapeutic potential of ⁶⁴CuCl₂ for the radionuclide cancer therapy of copper-avid tumors. Recently, ⁶⁴CuCl₂ was successfully used to image prostate cancer, bladder cancer, glioblastoma multiforme (GBM), and non-small cell lung carcinoma in humans. Copper cancer uptake was related to the expression of human copper transport 1 (hCTR1) on the cancer cell surface. Biodistribution, toxicology and radiation safety studies showed its radiation and toxicology safety. Based on the findings from the preclinical research studies, ⁶⁴CuCl₂ PET/CT also holds potential for the diagnostic imaging of human hepatocellular carcinoma (HCC), malignant melanoma, and the detection of the intracranial metastasis of copper-avid tumors based on the low physiological background of radioactive copper uptake in the brain. Full article

Copper radioisotopes are generally employed for cancer imaging and therapy when firmly coordinated via a chelating agent coupled to a tumor-seeking vector. However, the biologically triggered Cu²⁺-Cu⁺ redox switching may constrain the in vivo integrity of the resulting complex, leading to demetallation processes. This unsought pathway is expected to be hindered by chelators bearing N, O, and S donors which appropriately complements the borderline-hard and soft nature of Cu²⁺ and Cu⁺. In this work, the labelling performances of a series of S-rich polyazamacrocyclic chelators with [⁶⁴Cu]Cu²⁺ and the stability of the [⁶⁴Cu]Cu-complexes thereof were evaluated. Among the chelators considered, the best results were obtained with 1,7-bis [2-(methylsulfanyl)ethyl]-4,10,diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S). DO2A2S was labelled at high molar activities in mild reaction conditions, and its [⁶⁴Cu]Cu²⁺ complex showed excellent integrity in human serum over 24 h. Biodistribution studies in BALB/c nude mice performed with [⁶⁴Cu][Cu(DO2A2S)] revealed a behavior similar to other [⁶⁴Cu]Cu-labelled cyclen derivatives characterized by high liver and kidney uptake, which could either be ascribed to transchelation phenomena or metabolic processing of the intact complex. Full article

PET imaging has gained significant momentum in the last few years, especially in the area of oncology, with an increasing focus on metal radioisotopes owing to their versatile chemistry and favourable physical properties. Copper-61 (t_1/2 = 3.33 h, 61% β⁺, E_max = 1.216 MeV) provides unique advantages versus the current clinical standard (i.e., gallium-68) even though, until now, no clinical amounts of ⁶¹Cu-based radiopharmaceuticals, other than thiosemicarbazone-based molecules, have been produced. This study aimed to establish a routine production, using a standard medical cyclotron, for a series of widely used somatostatin analogues, currently labelled with gallium-68, that could benefit from the improved characteristics of copper-61. We describe two possible routes to produce the radiopharmaceutical precursor, either from natural zinc or enriched zinc-64 liquid targets and further synthesis of [⁶¹Cu]Cu-DOTA-NOC, [⁶¹Cu]Cu-DOTA-TOC and [⁶¹Cu]Cu-DOTA-TATE with a fully automated GMP-compliant process. The production from enriched targets leads to twice the amount of activity (3.28 ± 0.41 GBq vs. 1.84 ± 0.24 GBq at EOB) and higher radionuclidic purity (99.97% vs. 98.49% at EOB). Our results demonstrate, for the first time, that clinical doses of ⁶¹Cu-based radiopharmaceuticals can easily be obtained in centres with a typical biomedical cyclotron optimised to produce ¹⁸F-based radiopharmaceuticals. Full article

A synthetic procedure for the synthesis of azacrown ethers with a combination of pendant arms has been developed and the synthesized ligand, characterized by various techniques, was studied. The prepared benzoazacrown ether with hybrid pendant arms and its complexes with copper and lead cations were studied in terms of biomedical applications. Similarly to a fully acetate analog, the new one binds both cations with close stability constants, despite the decrease in both constants. The calculated geometry of the complexes correlate with the data from X-ray absorption and NMR spectroscopy. Coordination of both cations differs due to the difference between the ionic radii. However, these chelation modes provide effective shielding of cations in both cases, that was shown by the stability of their complexes in the biologically relevant media towards transchelation and transmetallation. Full article

Serum albumin binding moieties (ABMs) such as the Evans blue (EB) dye fragment and the 4-(p-iodophenyl)butyryl (IP) have been used to improve the pharmacokinetic profile of many radiopharmaceuticals. The goal of this work was to directly compare these two ABMs when conjugated to an integrin α_vβ₆ binding peptide (α_vβ₆-BP); a peptide that is currently being used for positron emission tomography (PET) imaging in patients with metastatic cancer. The ABM-modified α_vβ₆-BP peptides were synthesized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid (DOTA) chelator for radiolabeling with copper-64 to yield [⁶⁴Cu]Cu DOTA-EB-α_vβ₆-BP ([⁶⁴Cu]1) and [⁶⁴Cu]Cu DOTA-IP-α_vβ₆-BP ([⁶⁴Cu]2). Both peptides were evaluated in vitro for serum albumin binding, serum stability, and cell binding and internalization in the paired engineered melanoma cells DX3puroβ6 (α_vβ₆ +) and DX3puro (α_vβ₆ −), and pancreatic BxPC-3 (α_vβ₆ +) cells and in vivo in a BxPC-3 xenograft mouse model. Serum albumin binding for [⁶⁴Cu]1 and [⁶⁴Cu]2 was 53–63% and 42–44%, respectively, with good human serum stability (24 h: [⁶⁴Cu]1 76%, [⁶⁴Cu]2 90%). Selective α_vβ₆ cell binding was observed for both [⁶⁴Cu]1 and [⁶⁴Cu]2 (α_vβ₆ (+) cells: 30.3–55.8% and 48.5–60.2%, respectively, vs. α_vβ₆ (−) cells <3.1% for both). In vivo BxPC-3 tumor uptake for both peptides at 4 h was 5.29 ± 0.59 and 7.60 ± 0.43% ID/g ([⁶⁴Cu]1 and [⁶⁴Cu]2, respectively), and remained at 3.32 ± 0.46 and 4.91 ± 1.19% ID/g, respectively, at 72 h, representing a >3-fold improvement over the non-ABM parent peptide and thereby providing improved PET images. Comparing [⁶⁴Cu]1 and [⁶⁴Cu]2, the IP-ABM-α_vβ₆-BP [⁶⁴Cu]2 displayed higher serum stability, higher tumor accumulation, and lower kidney and liver accumulation, resulting in better tumor-to-organ ratios for high contrast visualization of the α_vβ₆ (+) tumor by PET imaging. Full article