New Macrobicyclic Chelator for the Development of Ultrastable ⁶⁴Cu-Radiolabeled Bioconjugate

Abstract

Ethylene cross-bridged cyclam with two acetate pendant arms, ECB-TE2A, is known to form the most kinetically stable (64)Cu complexes. However, its usefulness as a bifunctional chelator is limited because of its harsh radiolabeling conditions. Herein, we report new cross-bridged cyclam chelator for the development of ultrastable (64)Cu-radiolabeled bioconjugates. Propylene cross-bridged TE2A (PCB-TE2A) was successfully synthesized in an efficient way. The Cu(II) complex of PCB-TE2A exhibited much higher kinetic stability than ECB-TE2A in acid decomplexation studies, and also showed high resistance to reduction-mediated demetalation. Furthermore, the quantitative radiolabeling of PCB-TE2A with (64)Cu was achieved under milder conditions compared to ECB-TE2A. Biodistribution studies strongly indicate that the (64)Cu complexes of PCB-TE2A cleared out rapidly from the body with minimum decomplexation.

Phosphonate Pendant Armed Propylene Cross-Bridged Cyclam: Synthesis and Evaluation as a Chelator for Cu-64

“…In comparison, kidney uptake of PCB-TE2A at 30 min PI was 1.32 ± 0.35%ID/g, which was reduced to 15% and 3% of the initial activity at 4 and 24 h PI, respectively (0.21 ± 0.03%ID/g at 4 h PI and 0.04 ± 0.006%ID/g at 24 h PI). 12 The slow kidney clearance of 64 Cu-PCB-TE2P in comparison with that of 64 Cu-PCB-TE2A might be due to the difference in the overall charge of each Cu-complex. PCB-TE2P has −4 charge, which becomes −2 after complexation with Cu 2+ ions, whereas PCB-TE2A has −2 charge and becomes neutral after complexation with Cu 2+ .…”

“…9,12 First, the synthesized Cu-complex was evaluated in the acidcatalyzed half-life determination assay by using a spectrophotometer. After acid decomplexation of Cu-PCB-TE2P in 5 M HCl at 90°C, it did not show any change in absorption, even after 48 h, which strongly indicated that Cu-PCB-TE2P was highly stable under these conditions and suggested that harsher conditions were required for Cu-decomplexation.…”

Non-Cross-Bridged Tetraazamacrocyclic Chelator for Stable 64Cu-Based Radiopharmaceuticals

“…The current stability data were compared with those of Cu-TE2A and Cu-ECB-TE2A. 16,21 Approximately 2.7% and 1.6% of the intact Cu-MM-/DM-TE2A complexes were found at 4 and 14 h after incubation, respectively, whereas most of the Cu-TE2A complex degraded in <1 h in the same acid decomplexation experiment. The Cu-DM-TE2A showed even higher robustness than Cu-ECB-TE2A under this harsh acidic condition (Table 1).…”

Electrocatalytic Reduction of CO2by Copper (II) Cyclam Derivatives

“…The excellent resistance of Cu(II)-PCB-TE2A to reduction-induced demetalation is ascribed to thorough protection of Cu(II)-cyclam backbone by the two Cu-coordinating acetate groups as well as by a cross-bridging propylene moiety [17]. Cu(II)-PCB-TE2A, however, shows only marginal electrocatalytic activity for CO 2 reduction.…”

“…Cu(II)-cyclam was synthesized based on the similar method to Ni(II)-cyclam. PCB-cyclam and PCB-TE2A were synthesized according to the literature procedure [17].…”