AAZTA-Derived Chelators for the Design of Innovative Radiopharmaceuticals with Theranostic Applications

Abstract

With the development of 68Ga and 177Lu radiochemistry, theranostic approaches in modern nuclear medicine enabling patient-centered personalized medicine applications have been growing in the last decade. In conjunction with the search for new relevant molecular targets, the design of innovative chelating agents to easily form stable complexes with various radiometals for theranostic applications has gained evident momentum. Initially conceived for magnetic resonance imaging applications, the chelating agent AAZTA features a mesocyclic seven-membered diazepane ring, conferring some of the properties of both acyclic and macrocyclic chelating agents. Described in the early 2000s, AAZTA and its derivatives exhibited interesting properties once complexed with metals and radiometals, combining a fast kinetic of formation with a slow kinetic of dissociation. Importantly, the extremely short coordination reaction times allowed by AAZTA derivatives were particularly suitable for short half-life radioelements (i.e., 68Ga). In view of these particular characteristics, the scope of this review is to provide a survey on the design, synthesis, and applications in the nuclear medicine/radiopharmacy field of AAZTA-derived chelators.

Towards Clinical Development of Scandium Radioisotope Complexes for Use in Nuclear Medicine: Encouraging Prospects with the Chelator 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic Acid (DOTA) and Its Analogues

“…Several chelating agents for scandium have been described in the literature in addition to the commonly used DOTA [135][136][137][138][139][140][141][142][143][144][145][146] (Table 4), many of which constitute derivatives or structural analogues of DOTA, with the same (DO3AP, DO3AP PrA , DO3AP ABn , DO3AM-NI, NBD), smaller (H3mpatcn, NOTA, AAZTA), or larger (TETA) macrocyclic ring system, while others are non-cyclic counterparts (EDTA, DTPA, H4pypa). Note: The IUPAC names of all chelators included in this table can be found in the "Abbreviations" section.…”

Cyclotron production of 43Sc and 44gSc from enriched 42CaO, 43CaO, and 44CaO targets

“…Once radiochemically separated from the target material, 44g Sc has been successfully complexed and exhibited high in-vivo stability with the commonly used chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) ( Huclier-Markai, et al, 2014 ). As an alternative to DOTA, novel chelators designed and optimized for scandium include the heptadendate AAZTA ligands, the nonmacrocyclic H 4 pypa chelator, and the triaza-macrocycle-based picolinate-functionalized chelator H 3 mpatcn that can be labeled with scandium at room temperature ( Li, et al, 2020a ; Vaughn, et al, 2020a ; Li, et al, 2020b ; Vaughn, et al, 2020b ; Fersing, et al, 2022 ). In vivo and in vitro studies have investigated 44g Sc labeled with DOTA-based peptides ( Hernandez, et al, 2014 ; van der Meulen, et al, 2015 ; Eppard, et al, 2017 ; Singh, et al, 2017 ) and conjugated AAZTA-PSMA peptides ( Sinnes, et al, 2020 ; Ghiani, et al, 2021 ).…”

AAZTA‐Like Ligands Bearing Phenolate Arms as Efficient Chelators for 68Ga Labelling in vitro and in vivo

“…One of the advantages of the AAZTA‐like family is the intermediate characteristics of the chelator which is in between the linear and macrocyclic structure allowing both fast complexation kinetics and high kinetic inertness of the Ga(III) complex. To this end, bifunctional derivatives of AAZTA were used for conjugation to peptides (PSMA, RGD, minigastrin) showing accumulation in tumours of the corresponding 68 Ga 3+ chelates [21,23–26] . Modifications of the AAZTA structure were designed to obtain more rigid backbones such as in CyAAZTA [27,28] and PIDAZTA [29] (Figure 1), and thus more inert Ga(III) complexes, or to lower the denticity obtaining the hexadentate DATA ligands (Figure 1) to allow a better match with the hexacoordinate Ga(III) ion [20] .…”

“…[12,13] So far, several chelators have been proposed for 68 Ga labelling and conjugation to targeting vectors for molecular imaging PET applications. These chelators can be divided into three main classes: i) linear structures, among which HBED (N,N'-bis(2-hydroxybenzyl)ethylenediamine -N,N'-diacetic acid) [14] and CHXdedpa (CHX = cyclohexane, dedpa = 1,2-[[6-carboxy-pyridin-2-yl]-methylamino]ethane) [15] are the most used; ii) macrocyclic ligands belonging to the family of DOTA (1,4,7,10-tetraazacyclododecane tetraacetic acid) [16][17][18] and NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) [19] analogues, iii) mesocyclic chelators such as AAZTA (6-amino-6-methylperhydro-1,4-diazepine tetraacetic acid) [20] and derivatives [21,22] (Figure 1).…”

“…To this end, bifunctional derivatives of AAZTA were used for conjugation to peptides (PSMA, RGD, minigastrin) showing accumulation in tumours of the corresponding 68 Ga 3 + chelates. [21,[23][24][25][26] Modifications of the AAZTA structure were designed to obtain more rigid backbones such as in CyAAZTA [27,28] and PIDAZTA [29] (Figure 1), and thus more inert Ga(III) complexes, or to lower the denticity obtaining the hexadentate DATA ligands (Figure 1) to allow a better match with the hexacoordinate Ga(III) ion. [20] DATA m bifunctional derivatives were also conjugated to targeting vectors such as PSMA [30] or fibroblast activation protein inhibitor (FAP) [31] for tumour imaging.…”