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.
The 64Cu-labeled chelator was analyzed in vivo by positron emission tomography (PET) imaging to evaluate its biodistribution in a murine model at different acquisition times. For this purpose, nine 6-week-old female Balb/C nude strain mice underwent micro-PET imaging at three different time points after 64Cu-labeled chelator injection. Specifically, the mice were divided into group 1 (acquisition 1 h after [64Cu] chelator administration, n = 3 mice), group 2 (acquisition 4 h after [64Cu]chelator administration, n = 3 mice), and group 3 (acquisition 24 h after [64Cu] chelator administration, n = 3 mice). Successively, all PET studies were segmented by means of registration with a standard template space (3D whole-body Digimouse atlas), and 108 radiomics features were extracted from seven organs (namely, heart, bladder, stomach, liver, spleen, kidney, and lung) to investigate possible changes over time in [64Cu]chelator biodistribution. The one-way analysis of variance and post hoc Tukey Honestly Significant Difference test revealed that, while heart, stomach, spleen, kidney, and lung districts showed a very low percentage of radiomics features with significant variations (p-value < 0.05) among the three groups of mice, a large number of features (greater than 60% and 50%, respectively) that varied significantly between groups were observed in bladder and liver, indicating a different in vivo uptake of the 64Cu-labeled chelator over time. The proposed methodology may improve the method of calculating the [64Cu]chelator biodistribution and open the way towards a decision support system in the field of new radiopharmaceuticals used in preclinical imaging trials.
Gamma Knife treatment is an alternative to traditional brain surgery and whole-brain radiation therapy for treating cancers that are inaccessible via conventional treatments. To assess the effectiveness of Gamma Knife treatments, functional imaging can play a crucial role. The aim of this study is to evaluate new prognostic indices to perform an early assessment of treatment response to therapy using positron emission tomography imaging. The parameters currently used in nuclear medicine assessments can be affected by statistical fluctuation errors and/or cannot provide information on tumor extension and heterogeneity. To overcome these limitations, the Cumulative standardized uptake value (SUV) Histogram (CSH) and Area Under the Curve (AUC) indices were evaluated to obtain additional information on treatment response. For this purpose, the absolute level of [11C]-Methionine (MET) uptake was measured and its heterogeneity distribution within lesions was evaluated by calculating the CSH and AUC indices. CSH and AUC parameters show good agreement with patient outcomes after Gamma Knife treatments. Furthermore, no relevant correlations were found between CSH and AUC indices and those usually used in the nuclear medicine environment. CSH and AUC indices could be a useful tool for assessing patient responses to therapy.
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