Chelation of Theranostic Copper Radioisotopes with S-Rich Macrocycles: From Radiolabelling of Copper-64 to In Vivo Investigation

Abstract

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.

Is Smaller Better? Cu2+/Cu+ Coordination Chemistry and Copper-64 Radiochemical Investigation of a 1,4,7-Triazacyclononane-Based Sulfur-Rich Chelator

“…Heating to 95 °C considerably increased the performances of both chelators, obtaining a quantitative RCI at 50 MBq/nmol and nearly identical labeling behavior (Figure D). Also at neutral pH, NO3S outperformed the results previously obtained with DO4S since the latter achieved quantitative incorporation at the maximal molar activity of 10 MBq/nmol at both RT and 95 °C …”

“…Although NODAGA achieved quantitative labeling at nearly the same maximum molar activity as did NO3S (i.e., 2.5 MBq/nmol), it demonstrated a lower labeling efficiency (Figure A). If compared with DO4S (i.e., our previously best-performing full S-substituted polyazamacrocycle), then NO3S showed superior features of being able to achieve quantitative incorporation at molar activity more than 2-fold higher …”

“…If compared with DO4S (i.e., our previously best-performing full S-substituted polyazamacrocycle), then NO3S showed superior features of being able to achieve quantitative incorporation at molar activity more than 2-fold higher. 26 When the temperature was increased to 95 °C (Figure 9B), a slight enhancement of the performances of NO3S was observed (e.g., the quantitative labeling shifted from 2.5 MBq/ nmol to around 5 MBq/nmol), and for NODAGA, the effect of the temperature variation on the maximal molar activity was less impacting. However, an improvement in its labeling trend was observed (e.g., the RCI shifted from 25% at RT to 50% at 95 °C at 10 MBq/nmol) (Figure 9A,B).…”

“…Also at neutral pH, NO3S outperformed the results previously obtained with DO4S since the latter achieved quantitative incorporation at the maximal molar activity of 10 MBq/nmol at both RT and 95 °C. 26 The human serum stability of [ 64 Cu][Cu(NO3S)] 2+ was evaluated to assess its integrity in the presence of biologically relevant ligands and metal ions that can respectively transchelate and transmetalate the complex in vivo. The obtained results, compared with those obtained with NODAGA and DO4S (data for the latter were taken from our previous work 26 ), are shown in Figure 10.…”

A New Production Method of High Specific Activity Radionuclides Towards Innovative Radiopharmaceuticals: The Isolpharm Project

“…A simple set-up was proposed, bearing a 1" x 1" inch cylindrical detector with Lanthanum Bromo-Chloride (LBC), La2.85Cl0.15:Ce, scintillator crystal manufactured by SCIONIX, coupled to a HAMAMATSU R11102 PhotoMultiplier Tube (PMT). This system showed optimal Minimum Detectable Activity (MDA) within our region of interest (511 keV ± 3σ) at acquisition times ≤ 15 min, and it was successfully used in a preliminary biodistribution study of Cu-64 administered with DO2A2S chelator [19].…”