An enzymatic approach to bifunctional chelating agents

Minazzi, Paolo; Lattuada, Luciano; Menegotto, Ivan Guglielmo; Giovenzana, Giovanni B.

doi:10.1039/c4ob00810c

Cited by 17 publications

(13 citation statements)

References 35 publications

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“…AAZTA is a readily available mesocyclic chelating agent (Scheme ), with a remarkable affinity to d and f transition‐metal ions . Bifunctional AAZTA derivatives were recently reported and successfully applied to the preparation of 68 Ga conjugates for PET imaging . Prompted by these results, we investigated the potential application of AAZTA as a platform for the development of 44 Sc‐based PET imaging agents.…”

Section: Methodsmentioning

confidence: 99%

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AAZTA: An Ideal Chelating Agent for the Development of ⁴⁴Sc PET Imaging Agents

et al. 2017

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Unprecedented fast and efficient complexation of Sc was demonstrated with the chelating agent AAZTA (AAZTA=1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine) under mild experimental conditions. The robustness of the Sc(AAZTA) chelate and conjugated biomolecules thereof is further shown by in vivo PET imaging in healthy and tumor mice models. The new results pave the way towards development of efficient Sc-based radiopharmaceuticals using the AAZTA chelator.

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Section: Methodsmentioning

confidence: 99%

“…AAZTAi sareadily available mesocyclic chelating agent [19] (Scheme 1), with ar emarkable affinity to da nd f transition-metal ions. [20,21] Bifunctional AAZTAd erivatives were recently reported [22,23] and successfully applied to the Scheme 1. The chelating agents AAZTA, CNAAZTA, and DOTA.…”

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confidence: 99%

AAZTA: An Ideal Chelating Agent for the Development of ⁴⁴Sc PET Imaging Agents

et al. 2017

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“…The protected bifunctional chelating agent 1 was prepared according to ref. [24] while methyl 3aminodeoxycholate 2 was synthesized following the procedure reported in ref. [25].…”

Section: Chemistrymentioning

confidence: 99%

“…The preparation of Gd-AAZTA-MADEC is sketched in Scheme 1. The starting materials are the protected bifunctional derivative 1, recently prepared through a chemo-enzymatic approach [24], and the methyl ester of 3-aminodeoxycholic acid, the latter prepared from deoxycholic acid according to a procedure reported by Anelli et al [25]. Standard amide coupling between 1 and 2 using DCC/DMAP in dichloromethane yields the protected conjugate 3 in 64% yield.…”

Section: Synthesismentioning

confidence: 99%

Gd-AAZTA-MADEC, an improved blood pool agent for DCE-MRI studies on mice on 1 T scanners

et al. 2016

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A novel MRI blood-pool contrast agent (Gd-AAZTA-MADEC) has been compared with established blood pool agents for tumor contrast enhanced images and angiography. Synthesis, relaxometric properties, albumin binding affinity and pharmacokinetic profiles are reported. For in vivo studies, angiographic images and tumor contrast enhanced images were acquired on mice with benchtop 1T-MRI scanners and compared with MS-325, B22956/1 and B25716/1. The design of this contrast agent involved the elongation of the spacer between the targeting deoxycholic acid moiety and the Gd-AAZTA imaging reporting unit that drastically changed either the binding affinity to albumin (KA(HSA) = 8.3x10 5 M-1) and the hydration state of the Gd ion (q=2) in comparison to the recently reported B25716/1. The very markedly high binding affinity towards mouse and human serum albumins resulted in peculiar pharmacokinetics and relaxometric properties. The NMRD profiles clearly indicated that maximum efficiency is attainable at magnetic field strength of 1T. In vivo studies showed high enhancement of the vasculature and a prolonged accumulation inside tumor. The herein reported pre-clinical imaging studies show that a great benefit arises from the combination of a benchtop MRI scanner operating at 1T and the albuminbinding Gd-AAZTA-MADEC complex, for pursuing enhanced angiography and improved characterization of tumor vascular microenvironment.

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“…Other chelators such as 1,4,7-triazacyclononane, 1-glutaric acid-4,7 acetic acid (NODAGA) [ 4 ] have shown the potential for convenient preparation of 68 Ga-radiopharmaceuticals at room temperature; however, they cannot be used for other trivalent metals, in particular, those for radionuclide therapy applications. A novel and versatile alternative bifunctional chelator for radiopharmaceutical applications is 6-[bis(carboxymethyl)]amino]-6-(9-carboxynonyl)-1,4-diazepane-1,4-diacetic acid, tetra- t -butyl ester (AAZTA) [ 5 ]. AAZTA is a heptadentate ligand, based on the perhydro-1,4-diazepine scaffold enabling rapid metal coordination under mild conditions.…”

Section: Introductionmentioning

confidence: 99%

Influence of a novel, versatile bifunctional chelator on theranostic properties of a minigastrin analogue

et al. 2015

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Background6-[Bis(carboxymethyl)amino]-1,4-bis(carboxymethyl)-6-methyl-1,4-diazepane (AAZTA ) is a promising chelator with potential advantages over 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for radiopharmaceutical applications. Its mesocyclic structure enables fast radiolabelling under mild conditions with trivalent metals including not only 68Ga for positron emission tomography (PET) but also 177Lu and 111In for single-photon emission computed tomography (SPECT) and radionuclide therapy. Here, we describe the evaluation of a bifunctional AAZTA derivative conjugated to a model minigastrin derivative as a potential theranostic agent.MethodsAn AAZTA derivative with an aliphatic C9 chain as linker was coupled to a minigastrin, namely [AAZTA0, D-Glu1, desGlu2–6]-minigastrin (AAZTA-MG), and labelled with 68Ga, 177Lu and 111In. The characterisation in vitro included stability studies in different media and determination of logD (octanol/PBS). Affinity determination (IC50) and cell uptake studies were performed in A431-CCK2R cells expressing the human CCK2 receptor. μPET/CT and ex vivo biodistribution studies were performed in CCK2 tumour xenograft-bearing nude mice and normal mice.ResultsAAZTA-MG showed high radiochemical yields for 68Ga (>95 %), 177Lu (>98 %) and 111In (>98 %). The logD value of −3.7 for both [68Ga]- and [177Lu]-AAZTA-MG indicates a highly hydrophilic character. Stability tests showed overall high stability in solution with some degradation in human plasma for [68Ga]- and transchelation towards DTPA for and [177Lu]-AAZTA-MG. An IC50 value of 10.0 nM was determined, which indicates a high affinity for the CCK2 receptor. Specific cell uptake after 60 min was >7.5 % for [68Ga]-AAZTA-MG and >9.5 % for [177Lu]-AAZTA-MG, comparable to other DOTA-MG-analogues. μPET/CT studies in CCK2 receptor tumour xenografted mice not only revealed high selective accumulation in A431-CCK2R positive tumours of 68Ga-labelled AAZTA-MG (1.5 % ID/g in 1 h post injection) but also higher blood levels as corresponding DOTA-analogues. The 111In-labelled peptide had a tumour uptake of 1.7 % ID/g. Biodistribution in normal mice with the [177Lu]-AAZTA-MG showed a considerable uptake in intestine (7.3 % ID/g) and liver (1.5 % ID/g).ConclusionOverall, AAZTA showed interesting properties as bifunctional chelator for peptides providing mild radiolabelling conditions for both 68Ga and trivalent metals having advantages over the currently used chelator DOTA. Studies are ongoing to further investigate in vivo targeting properties and stability issues and the influence of spacer length on biodistribution of AAZTA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-015-0154-7) contains supplementary material, which is available to authorized users.

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An enzymatic approach to bifunctional chelating agents

Cited by 17 publications

References 35 publications

AAZTA: An Ideal Chelating Agent for the Development of ⁴⁴Sc PET Imaging Agents

AAZTA: An Ideal Chelating Agent for the Development of ⁴⁴Sc PET Imaging Agents

Gd-AAZTA-MADEC, an improved blood pool agent for DCE-MRI studies on mice on 1 T scanners

Influence of a novel, versatile bifunctional chelator on theranostic properties of a minigastrin analogue

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An enzymatic approach to bifunctional chelating agents

Cited by 17 publications

References 35 publications

AAZTA: An Ideal Chelating Agent for the Development of 44Sc PET Imaging Agents

AAZTA: An Ideal Chelating Agent for the Development of 44Sc PET Imaging Agents

Gd-AAZTA-MADEC, an improved blood pool agent for DCE-MRI studies on mice on 1 T scanners

Influence of a novel, versatile bifunctional chelator on theranostic properties of a minigastrin analogue

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AAZTA: An Ideal Chelating Agent for the Development of ⁴⁴Sc PET Imaging Agents

AAZTA: An Ideal Chelating Agent for the Development of ⁴⁴Sc PET Imaging Agents