Diana I. Rodrigues

Background: Prostate cancer (PCa) remains one of the most commonly diagnosed malignancies and a leading cause of cancer-related morbidity and mortality among men worldwide. Despite considerable progress in diagnostic and therapeutic modalities, conventional approaches often fall short in capturing disease heterogeneity and managing advanced or treatment-resistant cases. Over the past years, molecular imaging and targeted radionuclide therapy within a theranostic framework have emerged as powerful tools to potentially overcome these limitations. In this context, copper radioisotopes—particularly copper-61 (T _1/2 = 3.33 h; 61% β ⁺ ), copper-64 (T _1/2 = 12.7 h; 17% β ⁺ , 39% β ^– ), and copper-67 (T _1/2 = 2.58 d; 100% β ^– )—have garnered considerable attention due to their favorable half-lives, straightforward coordination chemistry, and optimal physical decay properties for both imaging and therapy. Main body: This review comprehensively examines the progress and prospects of copper-based radiopharmaceuticals for PCa theranostics, with particular emphasis on agents targeting prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR), the two most extensively studied and clinically relevant molecular targets in this setting. Alternative markers are also discussed as promising avenues to tackle disease heterogeneity and expand the clinical applicability of these conjugates. By consolidating preclinical and clinical evidence, we aim to identify current challenges and opportunities in the development of copper-based radiopharmaceuticals, and contribute to a paradigm shift toward the widespread clinical adoption of these novel radiopharmaceutical platforms for improved patient care. Conclusion: Copper-based radiopharmaceuticals represent a promising class of agents with the potential to refine PCa management. As research advances, these compounds are poised to enhance diagnostic precision and therapeutic efficacy, paving the way for more personalized strategies and favorable clinical outcomes.

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.

Amyloid-β protein precursor (AβPP) is a large transmembrane protein highly expressed in the central nervous system and cleavage of it can produce amyloid-β peptides (Aβ) involved in synaptic dysfunction and loss associated with cognitive impairment in Alzheimer's disease (AD). Surprisingly, little is known about the synaptic and sub-synaptic distribution of AβPP in different types of nerve terminals. We used total, synaptic, sub-synaptic, and astrocytic membrane preparations obtained from the hippocampus of adult rats to define the localization of AβPP, using two different antibodies against different AβPP epitopes. Western blot analysis revealed that AβPP was not significantly enriched in synaptosomal as compared to total membranes. Within synapses, AβPP immunoreactivity was more abundant in pre- (60 ± 4%) than post- (30 ± 5%) or extra-synaptic fractions (10 ± 2%). Immunocytochemical analysis of purified nerve terminals indicated that AβPP was more frequently associated with glutamatergic (present in 31 ± 4% of glutamatergic terminals) rather than with GABAergic (16 ± 3%) or cholinergic terminals (4 ± 1%, n = 4). We also observed a general lack of co-localization of AβPP and GFAP immunoreactivities in the hippocampus of sections of adult rat brain, albeit we could detect the presence of AβPP in gliosomes (vesicular specializations of astrocytic membranes), suggesting that AβPP has a heterogeneous localization restricted to certain regions of astrocytes. These results provide the first direct demonstration that AβPP is mostly distributed among glutamatergic rather than GABAergic or cholinergic terminals of the adult rat hippocampus, in remarkable agreement with the particular susceptibility to dysfunction and degeneration of glutamatergic synapses in early AD.

Cellular prion protein (PrP^C) is widely expressed in the brain. Although the precise role of PrP^C remains uncertain, it has been proposed to be a pivotal modulator of neuroplasticity events by regulating the glutamatergic and serotonergic systems. Here we report the existence of neurochemical and functional interactions between PrP^C and the dopaminergic system. PrP^C was found to co‐localize with dopaminergic neurons and in dopaminergic synapses in the striatum. Furthermore, the genetic deletion of PrP^C down‐regulated dopamine D₁ receptors and DARPP‐32 density in the striatum and decreased dopamine levels in the prefrontal cortex of mice. This indicates that PrP^C affects the homeostasis of the dopaminergic system by interfering differently in different brain areas with dopamine synthesis, content, receptor density and signaling pathways. This interaction between PrP^C and the dopaminergic system prompts the hypotheses that the dopaminergic system may be implicated in some pathological features of prion‐related diseases and, conversely, that PrP^C may play a role in dopamine‐associated brain disorders.