On the dissociation pathways of copper complexes relevant as PET imaging agents

N,N-Alkylation Clarifies the Role of N- and O-Protonated Intermediates in Cyclen-Based 64Cu Radiopharmaceuticals

“…Looking forward, there remains a clear need to develop more robust in vitro assays to help benchmark and guide designs for stable 64 Cu agents. Similar to a growing number of reports, ,,,− , our study reveals that several standard in vitro benchmarks for stability (e.g., acid-mediated dissociation, reductive-induced demetallation, and stability constants) were entirely inadequate to forecast the performance of these agents under more physiologically relevant conditions. N -protonated species of macrocyclic polyaminocarboxylates have been proposed as key reactive intermediates along the dissociation pathway; ,− however, the significant kinetic stability of Cu II (DO3A C4H8 ) toward transchelation and encouraging in vivo performance calls this into question.…”

“…27−31 Direct transchelation by biological ligands, 32,33 acid-mediated dissociation (hydrolysis), 34−36 and reduction-induced demetallation 37−39 have all been suggested as viable pathways for Cu II decomplexation in vitro and/or in vivo; however, identification of key intermediates along these pathways has proven challenging. 40 Over the past decades, several other classes of 64 Cu [Cu II ] chelators have been identified as suitable agents for PET. 4,12,13,41 Macrocyclic polyaminocarboxylates derived from cross-bridged (CB) cyclam provide impressive thermodynamic and kinetic stability through the constrained binding cavity; 37,42,43 however, these systems can require harsh and extended radiolabeling conditions incompatible with biological conjugating agents 44,45 without further modification.…”

“…[ 64 Cu]­[Cu II (DOTATATE)] , Detectnet (Figure ), was recently approved by the FDA and is currently the only 64 Cu agent indicated for use with PET for localization of somatostatin receptor positive neuroendocrine tumors in adults. − Successful tumor recognition requires that chelators maintain excellent stability in vivo, as delocalization of 64 Cu reduces imaging sensitivity (i.e., tumor recognition) and increases radiation exposure to off-target organs and tissues . Although H 4 DOTA , H 3 DO3A , and their derivatives are well known to form thermodynamically and kinetically stable complexes in vitro, a number of studies have indicated challenges and diminished stability with the corresponding radiochemical Cu II complexes. − Direct transchelation by biological ligands, , acid-mediated dissociation (hydrolysis), − and reduction-induced demetallation − have all been suggested as viable pathways for Cu II decomplexation in vitro and/or in vivo; however, identification of key intermediates along these pathways has proven challenging …”

Highly inert Cu(ii) complexes of C-aryl bifunctional cyclam-picolinates with remarkable 64Cu-labelling and biodistribution

“…A general trend of enhanced inertness of Cu( ii )-chelates was recently correlated with the positive charge of the complexes. 13 In our case, we found increased inertness when evolving from positive to neutral complexes by adding a protonatable function away from the metal centre, therefore suggesting a different path of improvement.…”

A Bridge too Far? Comparison of Transition Metal Complexes of Dibenzyltetraazamacrocycles with and without Ethylene Cross-Bridges: X-ray Crystal Structures, Kinetic Stability, and Electronic Properties

“…Cross-bridged tetraazamacrocycles that have an additional two-carbon bridge between non-adjacent nitrogen atoms of a tetraazamacrocycle, which are particularly rigid and lead to very kinetically stable metal complexes, have been extensively studied by Weisman [ 1 , 2 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ], Springborg [ 13 , 14 , 15 ], Hubin [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ], Archibald [ 24 , 25 , 26 , 27 , 28 , 29 , 30 ], Tripier [ 31 , 32 , 33 , 34 , 35 , 36 ], and others [ 37 , 38 , 39 ]. This stability conferred on these transition metal complexes shows great promise in such applications as homogeneous catalysis [ 40 , 41 , 42 , 43 ], inorganic drug candidates [ 20 , 24 , 26 , 27 , 44 , 45 , 46 ], and biomedical imaging agents [ ...…”