Decoration of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) with N‐oxides increases the T1 relaxivity of Gd‐complexes

Kerpa, Svenja; Schulze, Verena R.; Holzapfel, Malte; Cvancar, Lina; Fischer, Markus; Maison, Wolfgang

doi:10.1002/open.202300298

Cited by 3 publications

(2 citation statements)

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“…The good complexation properties of N -oxides have also been used by other researchers to assemble new Gd-based contrast agents for MRI. , In addition, N -oxides are strongly hydrated in an aqueous solution. Like other zwitterions, they can thus be used for conjugation to drugs to improve their solubility, increase their Stokes radius, and reduce unwanted tissue or protein binding. , Along these lines, the decoration of gadoteric acid (Dotarem) with four N -oxide functionalities (not involved in metal binding) led to the development of Gd-DOTA-NOx with almost three times higher relaxivity …”

Section: Drugs Containing N-oxide Groupsmentioning

confidence: 99%

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Medicinal Chemistry of Drugs with N-Oxide Functionalities

Kobus,

Friedrich,

Zorn

et al. 2024

J. Med. Chem.

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Molecules with N-oxide functionalities are omnipresent in nature and play an important role in Medicinal Chemistry. They are synthetic or biosynthetic intermediates, prodrugs, drugs, or polymers for applications in drug development and surface engineering. Typically, the N-oxide group is critical for biomedical applications of these molecules. It may provide water solubility or decrease membrane permeability or immunogenicity. In other cases, the N-oxide has a special redox reactivity which is important for drug targeting and/or cytotoxicity. Many of the underlying mechanisms have only recently been discovered, and the number of applications of N-oxides in the healthcare field is rapidly growing. This Perspective article gives a short summary of the properties of N-oxides and their synthesis. It also provides a discussion of current applications of N-oxides in the biomedical field and explains the basic molecular mechanisms responsible for their biological activity. ■ SIGNIFICANCE Relevance of N-oxides for Medicinal Chemistry:• N + −O − bonds are highly polar and form strong hydrogen bonds. They may be inert or reactive in biological systems depending on their substituents.• N-Oxide groups can be used to increase the solubility of drugs and decrease membrane permeability.• Many heteroaromatic and aniline-derived N-oxides are reduced enzymatically in vivo and find applications as hypoxia-activated prodrugs.• Polymeric N-oxides have excellent blood compatibility, are nonimmunogenic and are nonadhesive for microorganisms (stealth materials).

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Section: Drugs Containing N-oxide Groupsmentioning

confidence: 99%

“… 155 , 156 Along these lines, the decoration of gadoteric acid (Dotarem) with four N -oxide functionalities (not involved in metal binding) led to the development of Gd-DOTA-NOx with almost three times higher relaxivity. 157 …”

Section: Drugs Containing N -Oxide Groupsmentioning

confidence: 99%

Medicinal Chemistry of Drugs with N-Oxide Functionalities

Kobus,

Friedrich,

Zorn

et al. 2024

J. Med. Chem.

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Three Is a Magic Number: Tailored Clickable Chelators Used to Determine Optimal RGD-Peptide Multiplicity in αvβ6-Integrin Targeted ¹⁷⁷Lu-Labeled Cancer Theranostics

Rheinfrank,

Lebruška,

Stangl

et al. 2024

Bioconjugate Chem.

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The cellular adhesion receptor αvβ6-integrin is highly expressed in many cancers, e.g., pancreatic, lung, head-andneck, cervical, bladder, and esophageal carcinoma. Multimerization of αvβ6-integrin-specific RGD peptides increases the target affinity and retention but affects biodistribution and pharmacokinetics. Amide formation of the terminal carboxylic acid moieties of the square-symmetrical bifunctional chelator DOTPI with 3-azidopropylamine yields derivatives with 4, 3, and 2 terminal azides and zero, 1, and 2 remaining carboxylic acids, respectively, whereby formation of the 2-cis-isomer is preferred according to NMR investigation of the Eu(III)-complexes. Cu(II)-catalyzed alkyne− azide cycloaddition (CuAAC) of the alkyne-functionalized αvβ6-integrin binding peptide cyclo[YRGDLAYp(NMe)K(pent-4-ynoic amide)] (Tyr2) yields the respective di-, tri-, and tetrameric conjugates for Lu-177-labeling. In mice bearing αvβ6-integrinexpressing xenografts of H2009 (human lung adenocarcinoma) cells, the Lu-177-labeled trimer's tumor-to-blood ratio of 112 exceeds that of the tetramer (10.4) and the dimer (54). Co-infusion of gelofusine (succinylated gelatin) reduces the renal uptake of the trimer by 89%, resulting in a 10-fold better tumor-to-kidney ratio, while no improvement of that ratio is observed with arginine/ lysine, para-aminohippuric acid (PAH), and hydroxyethyl starch (HES) coinfusions. Since the Lu-177-labeled Tyr2-trimer outperforms the dimer and the tetramer, such trimers are considered the best lead structures for the ongoing development of αvβ6integrin targeted anticancer theranostics.

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Iodinated PSMA Ligands as XFI Tracers for Targeted Cell Imaging and Characterization of Nanoparticles

Kerpa,

Holzapfel,

Staufer

et al. 2024

IJMS

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Prostate cancer is the second most commonly diagnosed cancer in men worldwide. Despite this, current diagnostic tools are still not satisfactory, lacking sensitivity for early-stage or single-cell diagnosis. This study describes the development of small-molecule tracers for the well-known tumor marker prostate-specific membrane antigen (PSMA). These tracers contain a urea motif for PSMA-targeting and iodinated aromatic moieties to allow detection via X-ray fluorescence imaging (XFI). Tracers with a triiodobenzoyl moiety allowed the specific targeting and successful imaging of PSMA+ cell lines with XFI. The XFI-measured uptake of 7.88 × 10−18 mol iodine (I) per cell is consistent with the uptake of known PSMA tracers measured by other techniques such as inductively coupled plasma mass spectrometry (ICP-MS). This is the first successful application of XFI to tumor cell targeting with a small-molecule tracer. In addition, iodinated tracers were used for the characterization of quantum dots (QDs) conjugated to PSMA-targeting urea motifs. The resulting targeted QD conjugates were shown to selectively bind PSMA+ cell lines via confocal microscopy. The immobilized iodinated targeting vectors allowed the determination of the tracer/QD ratio via XFI and ICP-MS. This ratio is a key property of targeted particles and difficult to measure by other techniques.

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Decoration of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) with N‐oxides increases the T₁ relaxivity of Gd‐complexes

Cited by 3 publications

References 62 publications

Medicinal Chemistry of Drugs with N-Oxide Functionalities

Medicinal Chemistry of Drugs with N-Oxide Functionalities

Three Is a Magic Number: Tailored Clickable Chelators Used to Determine Optimal RGD-Peptide Multiplicity in αvβ6-Integrin Targeted ¹⁷⁷Lu-Labeled Cancer Theranostics

Iodinated PSMA Ligands as XFI Tracers for Targeted Cell Imaging and Characterization of Nanoparticles

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Decoration of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) with N‐oxides increases the T1 relaxivity of Gd‐complexes

Cited by 3 publications

References 62 publications

Medicinal Chemistry of Drugs with N-Oxide Functionalities

Medicinal Chemistry of Drugs with N-Oxide Functionalities

Three Is a Magic Number: Tailored Clickable Chelators Used to Determine Optimal RGD-Peptide Multiplicity in αvβ6-Integrin Targeted 177Lu-Labeled Cancer Theranostics

Iodinated PSMA Ligands as XFI Tracers for Targeted Cell Imaging and Characterization of Nanoparticles

Contact Info

Product

Resources

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Decoration of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) with N‐oxides increases the T₁ relaxivity of Gd‐complexes

Three Is a Magic Number: Tailored Clickable Chelators Used to Determine Optimal RGD-Peptide Multiplicity in αvβ6-Integrin Targeted ¹⁷⁷Lu-Labeled Cancer Theranostics