A Modular Approach towards the Synthesis of Target‐Specific MRI Contrast Agents

Verwilst, Peter; Eliseeva, Svetlana V.; Carron, Sophie; Elst, Luce Vander; Burtéa, Carmen; Dehaen, Geert; Laurent, Sophie; Binnemans, Koen; Müller, Robert N.; Parac‐Vogt, Tatjana N.; Borggraeve, Wim M. De

doi:10.1002/ejic.201100575

Cited by 20 publications

(31 citation statements)

References 58 publications

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“…Accordingly,C u II could be quickly and quantitatively removedf rom TRAP derivatives like 7 and 11 after CuAAC functionalization by the addition of excess NOTA and acidification to pH 2-3 or,e ven more conveniently,b y simply adding excessN OTA·3HCl. [48][49][50] Owing to the high thermodynamic stability and pronounced kinetic inertness of Ln III -DOTAc omplexes, [51] transmetalation with Cu II appearsn ot to be an issue here. Because scavengers like NOTAd on ot interfere with virtually any biogenic substrate, the transchelation approachr epresents av aluable alternative to sulfide-mediated demetalation.…”

Section: Demetalation:c U II Removalmentioning

confidence: 99%

A Practical Guide on the Synthesis of Metal Chelates for Molecular Imaging and Therapy by Means of Click Chemistry

Notni

Wester

2016

Chemistry A European J

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The copper-catalyzed cycloaddition of organic azides and alkynes (CuAAC) is one of the most popular reactions for rapid assembly of multifunctional molecular frameworks from commercially available building blocks. It is also attractive for synthesis of conjugates of multidentate chelate ligands (chelators) with molecular targeting vectors, such as peptides or proteins, which serve as precursors for labeling with metal radionuclides or are useful as MRI contrast agents after Gd(III) complexation. However, applicability of CuAAC for such purposes is complicated by formation of unwanted copper chelates. The alternative use of copper-free click chemistry, for example, the strain-promoted alkyne-azide cycloaddition (SPAAC) or the Diels-Alder reaction of tetrazines and strained alkenes, entails other specific challenges: Introduction of large, isomerically non-homogeneous and hydrophobic linker groups affects product homogeneity and can severely change pharmacokinetic profiles. Against this background, this review elucidates scope and applicability of both Cu-catalyzed and Cu-free alkyne-azide cycloadditions pertinent to the elaboration of radiometal chelates and MRI contrast agents, with an emphasis on strategies to tackle the problem of copper complexation during CuAAC.

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Section: Demetalation:c U II Removalmentioning

confidence: 99%

A Practical Guide on the Synthesis of Metal Chelates for Molecular Imaging and Therapy by Means of Click Chemistry

Notni

Wester

2016

Chemistry A European J

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“…Research toward the development of targeted CAs has been ongoing, with most efforts directed toward conjugation of a CA to specific antibodies or a peptide. 2,3 …”

Section: Introductionmentioning

confidence: 99%

cRGD Peptide-Conjugated Icosahedral closo-B₁₂^2- Core Carrying Multiple Gd³⁺-DOTA Chelates for α_vβ₃ Integrin-Targeted Tumor Imaging (MRI)

Goswami

Cai

et al. 2013

Inorg. Chem.

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A vertex-differentiated icosahedral closo-B122− core was utilized to construct a αvβ3 integrin receptor-targeted (via cRGD peptide) high payload MRI contrast agent (CA-12) carrying 11 copies of Gd3+-DOTA chelates attached to the closo-B122− surface via suitable linkers. The resulting polyfunctional MRI contrast agent possessed a higher relaxivity value per-Gd compared to Omniscan, a small molecular contrast agent commonly used in clinical settings. The αvβ3 integrin receptor specificity of CA-12 was confirmed via in vitro cellular binding experiments and in vivo MRI of mice bearing human PC-3 prostate cancer xenografts. Integrin αvβ3-positive MDA-MB-231 cells exhibited 300% higher uptake of CA-12 than αvβ3-negative T47D cells. Serial T1-weighted MRI showed superior contrast enhancement of tumors by CA-12 compared to both a non-targeted 12-fold Gd3+-DOTA closomer control (CA-7) and Omniscan. Contrast enhancement by CA-12 persisted for 4 h post-injection, and subsequent enhancement of kidney tissue indicated a renal elimination route similar to Omniscan. No toxic effects of CA-12 were apparent in any mice for up to 24 h post-injection. Post-mortem ICP-OES analysis at 24 hours detected no residual Gd in any of the tissue samples analyzed.

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“…40,76 The following step involves the reaction with 2-(Boc-amino)ethyl bromide and subsequent deprotection of the obtained product with TFA that results in the product, DO3A-ethylamine (DO3A-EA) (3). It is a multistep synthesis starting from cyclen, which is treated with tert-butyl bromoacetic acid to yield DO3A-t Bu (1).…”

Section: Resultsmentioning

confidence: 99%

“…Altering the tumbling rate of the complex has been widely used as a method for enhancing the proton relaxivities. [21][22][23][37][38][39][40] Lanthanide ions have very interesting optical properties since they exhibit sharp emission lines and have long luminescence lifetimes. 25 Due to the high spatial resolution, the lack of ionizing radiation and penetration limitations, MRI is widely used as a preoperative technique to visualize the soft tissue in the human body.…”

Section: Introductionmentioning

confidence: 99%

Assembly of near infra-red emitting upconverting nanoparticles and multiple Gd(iii)-chelates as a potential bimodal contrast agent for MRI and optical imaging

Carron

Li²,

Elst

et al. 2015

Dalton Trans.

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Linking multiple paramagnetic gadolinium(III)-chelates based on the 2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]acetate (DOTA) ligand to the surface of NaGdF4:Yb(3+),Tm(3+) upconverting nanoparticles with an average particle size of 20 nm resulted in an assembly that has favorable properties for bimodal Magnetic Resonance Imaging (MRI) and Optical Imaging (OI). An improved synthetic pathway was used to couple the paramagnetic precursor to the nanoparticles. The nanoparticles were rendered water dispersible via citrate capping, leaving one acid group free for amide coupling with the mono-amino precursor of the DOTA ligand. Luminescence spectroscopy measurements have shown that the excitation of the nanoconstruct at 980 nm resulted in intense upconverted emission of thulium(III) at 800 nm. The assembly of several paramagnetic centers on the nanoparticle scaffold reduces the overall tumbling rate, resulting in enhanced longitudinal relaxation times and improved relaxivity. The proton NMRD profiles show a characteristic hump at higher frequencies, which is caused by the slow rotation of the nanoconstruct, resulting in r1 values of 25 mM(-1) s(-1) per gadolinium(III)-ion at 60 MHz and 310 K. This is a significant improvement compared to the Gd-DO3A-ethylamine precursor (4) for which a value of r1 of 3.23 mM(-1) s(-1) was observed under the same conditions. Theoretical fitting by two different approaches showed an increase of τR from 57.3 ps for the Gd-DO3A-ethylamine precursor (4) to 392.0 ps for the nanoconstruct, which is responsible for the overall substantial increase in relaxivity.

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A Modular Approach towards the Synthesis of Target‐Specific MRI Contrast Agents

Cited by 20 publications

References 58 publications

A Practical Guide on the Synthesis of Metal Chelates for Molecular Imaging and Therapy by Means of Click Chemistry

A Practical Guide on the Synthesis of Metal Chelates for Molecular Imaging and Therapy by Means of Click Chemistry

cRGD Peptide-Conjugated Icosahedral closo-B₁₂^2- Core Carrying Multiple Gd³⁺-DOTA Chelates for α_vβ₃ Integrin-Targeted Tumor Imaging (MRI)

Assembly of near infra-red emitting upconverting nanoparticles and multiple Gd(iii)-chelates as a potential bimodal contrast agent for MRI and optical imaging

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A Modular Approach towards the Synthesis of Target‐Specific MRI Contrast Agents

Cited by 20 publications

References 58 publications

A Practical Guide on the Synthesis of Metal Chelates for Molecular Imaging and Therapy by Means of Click Chemistry

A Practical Guide on the Synthesis of Metal Chelates for Molecular Imaging and Therapy by Means of Click Chemistry

cRGD Peptide-Conjugated Icosahedral closo-B122- Core Carrying Multiple Gd3+-DOTA Chelates for αvβ3 Integrin-Targeted Tumor Imaging (MRI)

Assembly of near infra-red emitting upconverting nanoparticles and multiple Gd(iii)-chelates as a potential bimodal contrast agent for MRI and optical imaging

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Product

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cRGD Peptide-Conjugated Icosahedral closo-B₁₂^2- Core Carrying Multiple Gd³⁺-DOTA Chelates for α_vβ₃ Integrin-Targeted Tumor Imaging (MRI)