Synthesis and Evaluation of Radioiodinated Acyloxymethyl Ketones as Activity-Based Probes for Cathepsin B

Edem, Patricia E.; Czorny, Shannon; Valliant, John F.

doi:10.1021/jm501357r

Cited by 22 publications

(19 citation statements)

References 51 publications

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“…Notably, this enzyme can be expressed as an inactive proenzyme, and therefore detection of the enzyme's activity may be more informative than monitoring the enzyme's expression (23). Contrast agents for other imaging modalities can also detect cathepsin B activity, including optical imaging agents and radionuclide agents that typically require concentrations in the nanomolar concentration range (24,25). However, as shown in these studies, the detection of the activity of a nanomolar concentration of cathepsin B enzyme is feasible if enzyme catalysis can rapidly convert a high concentration of the agent to product.…”

Section: Discussionmentioning

confidence: 99%

A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals

Hingorani

Montano

Randtke

et al. 2015

Contrast Media & Molecular

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CatalyCEST MRI can detect enzyme activity by monitoring the change in chemical exchange with water after a contrast agent is cleaved by an enzyme. Often these molecules use paramagnetic metals and are delivered with an additional non-responsive reference molecule. To improve this approach for molecular imaging, a single diamagnetic agent with enzyme-responsive and enzyme-unresponsive CEST signals was synthesized and characterized. The CEST signal from the aryl amide disappeared after cleavage of a dipeptidyl ligand with cathepsin B, while a salicylic acid moiety was largely unresponsive to enzyme activity. The ratiometric comparison of the two CEST signals from the same agent allowed for concentration independent measurements of enzyme activity. The chemical exchange rate of the salicylic acid moiety was unchanged after enzyme catalysis, which further validated that this moiety was enzyme-unresponsive. The temperature dependence of the chemical exchange rate of the salicylic acid moiety was non-Arrhenius, suggesting a two-step chemical exchange mechanism for salicylic acid. The good detection sensitivity at low saturation power facilitates clinical translation, along with the potentially low toxicity of a non-metallic MRI contrast agent. The modular design of the agent constitutes a platform technology that expands the variety of agents that may be employed by catalyCEST MRI for molecular imaging.

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Section: Discussionmentioning

confidence: 99%

A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals

Hingorani

Montano

Randtke

et al. 2015

Contrast Media & Molecular

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“…Having developed the platform for functionalizing the dendrimer periphery under mild conditions, and radiolabeling the core with 99m Tc, we investigated the ability to introduce multiple AOMK targeting agents for cathepsin B at the dendrimer periphery. This was accomplished by converting the free amine of the lysine residue on AOMK, prepared according to literature procedures, to an azide functionality via amidation with either an aliphatic azide‐terminated acid of various length, or a commercially available triethylene glycol unit bearing an azide on one end and an acid group on the other (Scheme ). In order to determine the effect of spacer length, the aliphatic chains used for amidation included a C 2 , C 4 , or C 6 chain length.…”

Section: Resultsmentioning

confidence: 99%

“…The AOMK analogues bearing C 2 , C 4 , and C 6 spacers ( 28a–c ) were first coupled to [ReDPA‐G1‐(yne) 2 ] + ( 17 ) to produce first‐generation dendrimers 31 – 33 (Figure ), allowing determination of the effect of spacer length. A colorimetric kinetic assay previously employed to evaluate iodinated AOMK derivatives was used to determine the binding affinities of the non‐radioactive imaging agent analogues (for details, see Supporting Information). Briefly cathepsin B, isolated from human liver, was added to solutions of the colorimetric cathepsin B substrate (Z‐RR‐pNA) and the AOMK derivatives.…”

Section: Resultsmentioning

confidence: 99%

“…Lead compounds were then radiolabeled and tested in murine tumor models. Although these compounds were able to detect cathepsin B activity in vitro, they underwent deiodination in vivo, thus exhibiting low tumor uptake . Encouraged by this work, we set out to derivatize the periphery of a PMPA dendrimer with multiple AOMK ligands using different length linkers, with the aim of investigating the effect of linker chemistry and multivalent interactions on affinity to cathepsin B.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of Polyester Dendritic Scaffolds for Biomedical Applications

Sadowski

Edem

Valliant

et al. 2016

Macromolecular Bioscience

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Using a well-defined poly(2,2-bis(hydroxymethyl)propanoic acid) dendrimer scaffold, a series of G1 to G3 dendrons is functionalized at the periphery with alkynes to enable "Click" functionalization via the copper-catalyzed alkyne-azide cycloaddition (CuAAC). The resulting dendrons are further functionalized at the core with a dipicolylamine (DPA) moiety to enable radiolabeling with Tc for molecular imaging applications. Efficient CuAAC coupling is achieved using an azide-functionalized triethylene glycol monomethyl ether (TEG-N ). Removal of copper from the DPA ligand is successfully performed on G1 and G2 dendrimers prior to radiolabeling with Tc. Radiolabeling of the G3 dendrimer is accomplished via transmetallation of the [CuDPA] ligand with Tc, further demonstrating the feasibility of the synthetic strategies in the preparation of dendritic imaging agents. Subsequent attachment of an acyloxymethyl ketone (AOMK) derivative for targeting of cathepsin B is also explored. Despite demonstrating the ability to ligate multiple AOMK ligands, the AOMK-dendrimer conjugates are not able to bind to cathepsin B, which may be attributed to steric hindrance at the dendrimer periphery.

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“…The octanol-water partition coefficient (Log D) was measured in a similar manner previously described [43].…”

Section: Determination Of Log D (Ph 74)mentioning

confidence: 99%

Evaluation of a 68Ga-Labeled DOTA-Tetrazine as a PET Alternative to 111In-SPECT Pretargeted Imaging

et al. 2020

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The bioorthogonal reaction between a tetrazine and strained trans-cyclooctene (TCO) has garnered success in pretargeted imaging. This reaction was first validated in nuclear imaging using an 111In-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-linked bispyridyl tetrazine (Tz) ([111In]In-DOTA-PEG11-Tz) and a TCO functionalized CC49 antibody. Given the initial success of this Tz, it has been paired with TCO functionalized small molecules, diabodies, and affibodies for in vivo pretargeted studies. Furthermore, the single photon emission tomography (SPECT) radionuclide, 111In, has been replaced with the β-emitter, 177Lu and α-emitter, 212Pb, both yielding the opportunity for targeted radiotherapy. Despite use of the ‘universal chelator’, DOTA, there is yet to be an analogue suitable for positron emission tomography (PET) using a widely available radionuclide. Here, a 68Ga-labeled variant ([68Ga]Ga-DOTA-PEG11-Tz) was developed and evaluated using two different in vivo pretargeting systems (Aln-TCO and TCO-CC49). Small animal imaging and ex vivo biodistribution studies were performed and revealed target specific uptake of [68Ga]Ga-DOTA-PEG11-Tz in the bone (3.7 %ID/g, knee) in mice pretreated with Aln-TCO and tumor specific uptake (5.8 %ID/g) with TCO-CC49 in mice bearing LS174 xenografts. Given the results of this study, [68Ga]Ga-DOTA-PEG11-Tz can serve as an alternative to [111In]In-DOTA-PEG11-Tz.

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Synthesis and Evaluation of Radioiodinated Acyloxymethyl Ketones as Activity-Based Probes for Cathepsin B

Cited by 22 publications

References 51 publications

A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals

A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals

Synthesis of Polyester Dendritic Scaffolds for Biomedical Applications

Evaluation of a 68Ga-Labeled DOTA-Tetrazine as a PET Alternative to 111In-SPECT Pretargeted Imaging

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