Equilibrium, Kinetic and Structural Properties of Gallium(III) and Some Divalent Metal Complexes Formed with the New DATA^m and DATA^5m Ligands

Abstract

Abstract:The development of 68 Ge/ 68 Ga generators has made the positron emitting 68 Ga isotope widely accessible, raising interest in new chelate complexes of Ga 3+ . ). The stability constants of Ga(DATA m ) and Ga(DATA 5m ) complexes are slightly higher than those of the Ga(AAZTA). The species distribution calculations indicate the predominance of Ga(L)OH mixed hydroxo complexes at physiological pH. The 1 H-and 71 Ga-NMR studies provided information about the coordinated functional groups of ligands and on the kinetics of exchange between the Ga(L) and Ga(L)OH complexes. The transmetallation reactions between the Ga(L) complexes and Cu 2+ -citrate (6<pH<8.5) occur through both spontaneous and OH --assisted dissociation of the Ga(L)OH species. At pH=7.4 and 25 °C, the half lives of the dissociation of Ga(DATA m ), Ga(DATA 5m ) and Ga(AAZTA) are 11 h, 44 h and 24 h, respectively. Similar half-lifes have been obtained for the ligand exchange reactions between the Ga(L)OH complexes and transferrin. The equilibrium and kinetic data indicate that the Ga(DATA 5m ) complex is a good candidate as a 68 Ga-based radiodiagnostic.

PIDAZTA: Structurally Constrained Chelators for the Efficient Formation of Stable Gallium‐68 Complexes at Physiological pH

“…Generally the line width of 71 Ga NMR signals ( 71 Ga is a quadrupolar nucleus) is strongly influenced by the symmetry of Ga III complexes ([Ga(DATA m )]: δ Ga =129 ppm, ν 1/2 =1000 Hz; [Ga(CyAAZTA)] − : δ Ga =119 ppm, ν 1/2 =4700 Hz, 308 K; and [Ga(AAZTA)] − : δ Ga =118 ppm, ν 1/2 =2200 Hz) . Moreover, the broadening or sharpening of the 71 Ga NMR signal could be interpreted by the interaction of the nuclear quadrupole moment with the electric field gradient at the 71 Ga nucleus .…”

“…Generally the line width of 71 Ga NMRs ignals ( 71 Ga is aq uadrupolarn ucleus) is strongly influenced by the symmetry of Ga III complexes ([Ga(DATA m )]: d Ga = 129 ppm, n1 = 2 = 1000 Hz;[ Ga-(CyAAZTA)] À : d Ga = 119ppm, n1 = 2 = 4700 Hz, 308 K; and [Ga-(AAZTA)] À : d Ga = 118ppm, n1 = 2 = 2200 Hz). [9,17,21] Moreover,t he broadening or sharpening of the 71 Ga NMR signal could be interpreted by the interaction of the nuclearq uadrupole momentw itht he electric field gradienta tt he 71 Ga nucleus. [27] At pH 3.5, the 71 Ga NMR signals of [Ga(L1/L2)] complexes are very broad and not observable, as ar esult of the asymmetric coordination environmento ft he Ga 3 + ion provided by the rigid structure of L1/L2 ( Figure S8 and S10).…”

“…For this reason, the preparation of AAZTA derivatives with a lower denticity, termed DATAs (Figure ) and different coordinating arms was reported to better understand the role of donor groups in the coordination of the classically hexacoordinated Ga III . The results of the study on their coordination properties highlighted the role of the side arms (number and steric hindrance), and even more importantly, the ring substitution pattern, on the overall stability of the corresponding Ga III chelates . For example, the change from R=CH 3 to R=Ph in the structure of DATA affects the conformational population of the seven‐membered ring and accordingly the affinity for the metal ion .…”

“…[14] Moreover,s tructural studies were devoted to elucidating the coordination behavior of the 1,4-diazepane ring and the carboxymethyl side arms of AAZTAt owards Ga III .F or this reason, the preparationo fA AZTAd erivatives with al ower denticity,t ermedD ATAs [15] (Figure 1) and different coordinating arms [16] was reportedt ob etter understand the role of donor groups in the coordinationo ft he classically hexacoordinated Ga III .T he resultso ft he study on their coordination properties highlighted the role of the side arms (number and steric hindrance), and even more importantly,t he ring substitution pattern, on the overall stability of the corresponding Ga III chelates. [17,18] For example, the change from R = CH 3 to R = Ph in the structure of DATA affects the conformational population of the seven-membered ring and accordingly the affinity for the metal ion. [19,20] Ac areful design of the structure of the ligand is therefore crucial in thes earch for improved and more efficient chelating agents for Ga III .…”

Evaluation of a Bispidine‐Based Chelator for Gallium‐68 and of the Porphyrin Conjugate as PET/PDT Theranostic Agent

“…[10,11] The triazacyclononane derivative (NOTA), its analogue with phosphinic pendant arms (TRAP) and the acyclicc helator H 2 dedpa also need acidic conditions but no heating. [6,[12][13][14] All these chelators are however subjectt oc ompetition with Cu II and Zn II , [15,16] al-thoughT RAP displaysa napparent improved selectivity for Ga III . [13] 6-amino-1,4-diazepine triacetate (DATA)c helators [17] as well as siderophores (such as deferoxamine), [18] N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) [18] and tris(hydroxypyridinone) (THP) [18] have the advantage to be radiolabeled in aw ide pH range,T HP being the most promising as quantitative radiochemicaly ields can be obtained in mild conditions.…”