AAZTA: The rise of mesocyclic chelating agents for metal coordination in medicine

Travagin, Fabio; Lattuada, Luciano; Giovenzana, Giovanni B.

doi:10.1016/j.ccr.2021.213908

Cited by 10 publications

(10 citation statements)

References 169 publications

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“…8 Such favorable properties have promoted the development of several GdAAZTA derivatives with improved relaxivity, 11 which have found interesting applications in preclinical MRI studies. 12 In particular, the evidence that high molecular weight, slowly tumbling molecules provide greater r 1 values in the 0.5−1.5 T range of magnetic field strengths has driven the design of several GdAAZTA macromolecular systems, where the chelate is either covalently bound to large substrates or forms noncovalent macromolecular adducts. For instance, substantial efforts have been made in developing (i) dimeric, 13,14 multimeric, or dendrimeric derivatives alone, 15,16 or grafted to PEGylated mesoporous silica nanoparticles, 17 and (ii) lipophilic GdAAZTA complexes capable of assembling in supramolecular aggregates, such as micelles or liposomes, 18 which can achieve relaxivity values up to 10 times higher than those of the monomeric species.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Such favorable properties have promoted the development of several GdAAZTA derivatives with improved relaxivity, which have found interesting applications in preclinical MRI studies . In particular, the evidence that high molecular weight, slowly tumbling molecules provide greater r 1 values in the 0.5–1.5 T range of magnetic field strengths has driven the design of several GdAAZTA macromolecular systems, where the chelate is either covalently bound to large substrates or forms noncovalent macromolecular adducts.…”

Section: Introductionmentioning

confidence: 99%

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Derivatives of GdAAZTA Conjugated to Amino Acids: A Multinuclear and Multifrequency NMR Study

et al. 2022

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The GdAAZTA (AAZTA = 6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid) complex represents a platform of great interest for the design of innovative MRI probes due to its remarkable magnetic properties, thermodynamic stability, kinetic inertness, and high chemical versatility. Here, we detail the synthesis and characterization of new derivatives functionalized with four amino acids with different molecular weights and charges: l -serine, l -cysteine, l -lysine, and l -glutamic acid. The main reason for conjugating these moieties to the ligand AAZTA is the in-depth study of the chemical properties in aqueous solution of model compounds that mimic complex structures based on polypeptide fragments used in molecular imaging applications. The analysis of the 1 H NMR spectra of the corresponding Eu(III)-complexes indicates the presence of a single isomeric species in solution, and measurements of the luminescence lifetimes show that functionalization with amino acid residues maintains the hydration state of the parent complex unaltered ( q = 2). The relaxometric properties of the Gd(III) chelates were analyzed by multinuclear and multifrequency NMR techniques to evaluate the molecular parameters that determine their performance as MRI probes. The relaxivity values of all of the novel chelates are higher than that of GdAAZTA over the entire range of applied magnetic fields because of the slower rotational dynamics. Data obtained in reconstituted human serum indicate the occurrence of weak interactions with the proteins, which result in larger relaxivity values at the typical imaging fields. Finally, all of the new complexes are characterized by excellent chemical stability in biological matrices over time, by the absence of transmetallation processes, or the formation of ternary complexes with oxyanions of biological relevance. In particular, the kinetic stability of the new complexes, measured by monitoring the release of Gd 3+ in the presence of a large excess of Zn 2+ , is ca. two orders of magnitude higher than that of the clinical MRI contrast agent GdDTPA.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Derivatives of GdAAZTA Conjugated to Amino Acids: A Multinuclear and Multifrequency NMR Study

et al. 2022

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“…The vicinal positioning of all three nitrogen atoms and their symmetric arrangement play a key role in the formation of stable metal complexes of native PTA with different chelation configurations [7] . Additional exploitation of the valuable coordinating properties of PTA comes from the preparation of substituted derivatives with higher denticity, such as tripodal chelating agents, [8] the polyaminocarboxylic 1,2,3‐propanetriamine‐ N,N,N’,N’,N”,N” ‐hexaacetic acid, [9] or its incorporation in conformationally constrained derivatives such as the efficient 6‐amino‐1,4‐diazepane (“AAZTA”) based chelators [10] …”

Section: Introductionmentioning

confidence: 99%

“…[7] Additional exploitation of the valuable coordinating properties of PTA comes from the preparation of substituted derivatives with higher denticity, such as tripodal chelating agents, [8] the polyaminocarboxylic 1,2,3-propanetriamine-N,N,N',N',N",N"-hexaacetic acid, [9] or its incorporation in conformationally constrained derivatives such as the efficient 6-amino-1,4-diazepane ("AAZTA") based chelators. [10] In its nearly 150 years history, different synthetic approaches have been developed for the preparation of PTA, briefly summarised in Scheme 2, none of them suitable for a largescale preparation.…”

Section: Introductionmentioning

confidence: 99%

A Concise and Safe Synthesis of 1,2,3‐Propanetriamine (PTA)

Travagin

Giovenzana

2022

Eur J Org Chem

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1,2,3‐Propanetriamine (PTA) is the simplest aliphatic vicinal triamine, a key compound in coordination chemistry and for the preparation of polymers and for many other important applications. Despite its simple structure and its sesquicentennial history, the preparations of PTA have always been elaborate, hazardous, and low yielding. In this article a concise, safe and inexpensive synthesis of PTA is presented. PTA is prepared by a nitro‐Mannich reaction between dibenzylamine, nitromethane and paraformaldehyde, followed by a catalytic reduction‐debenzylation with Pearlman's catalyst leading to the desired triamine in 73 % yield over two steps. The procedure is amenable for larger‐scale preparations.

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“…[14] The coordination chemistry of Bi III with polyaminocarboxylic CAs is scarcely investigated, and no systematic investigation has been reported on the complexation of this metal ion with mesocyclic chelating agents. Among them, 6amino-6-methylperhydro-1,4-diazepinetetraacetic acid (AAZTA) [15] proved to be an efficient coordinating system for several metal ions in the lanthanoids, transition and post-transition metals. [16,17] Thanks to its simply editable structure, it lends itself to many modifications with the aim of tuning its chelating properties [18][19][20] and of preparing bifunctional derivatives for conjugation purposes.…”

Section: Introductionmentioning

confidence: 99%

Boosting Bismuth(III) Complexation for Targeted α‐Therapy (TAT) Applications with the Mesocyclic Chelating Agent AAZTA**

Horvath

Vágner²,

Szikra³

et al. 2022

Angewandte Chemie

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Targeted α therapy (TAT) is a promising tool in the therapy of cancer. The radionuclide 213BiIII shows favourable physical properties for this application, but the fast and stable chelation of this metal ion remains challenging. Herein, we demonstrate that the mesocyclic chelator AAZTA quickly coordinates BiIII at room temperature, leading to a robust complex. A comprehensive study of the structural, thermodynamic and kinetic properties of [Bi(AAZTA)]− is reported, along with bifunctional [Bi(AAZTA‐C4‐COO−)]2− and the targeted agent [Bi(AAZTA‐C4‐TATE)]−, which incorporates the SSR agonist Tyr3‐octreotate. An unexpected increase in the stability and kinetic inertness of the metal chelate was observed for the bifunctional derivative and was maintained for the peptide conjugate. A cyclotron‐produced 205/206Bi mixture was used as a model of 213Bi in labelling, stability, and biodistribution experiments, allowing the efficiency of [213Bi(AAZTA‐C4‐TATE)]− to be estimated. High accumulation in AR42J tumours and reduced kidney uptake were observed with respect to the macrocyclic chelate [213Bi(DOTA‐TATE)]−.

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AAZTA: The rise of mesocyclic chelating agents for metal coordination in medicine

Cited by 10 publications

References 169 publications

Derivatives of GdAAZTA Conjugated to Amino Acids: A Multinuclear and Multifrequency NMR Study

Derivatives of GdAAZTA Conjugated to Amino Acids: A Multinuclear and Multifrequency NMR Study

A Concise and Safe Synthesis of 1,2,3‐Propanetriamine (PTA)

Boosting Bismuth(III) Complexation for Targeted α‐Therapy (TAT) Applications with the Mesocyclic Chelating Agent AAZTA**

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