Radiolabeled B9958 Derivatives for Imaging Bradykinin B1 Receptor Expression with Positron Emission Tomography: Effect of the Radiolabel–Chelator Complex on Biodistribution and Tumor Uptake

Zhang, Zhengxing; Amouroux, Guillaume; Pan, Jinhe; Jenni, Silvia; Zeisler, Jutta; Zhang, Chengcheng; Liu, Zhibo; Perrin, David M.; Bénard, François; Lin, Kuo-Chi

doi:10.1021/acs.molpharmaceut.6b00428

Cited by 14 publications

(25 citation statements)

References 25 publications

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“…C18 Sep-Pak cartridges (1 cm 3 , 50 mg) were obtained from Waters (Milford, MA, USA). 68 Ga was eluted from an iThemba Laboratories (Somerset West, South Africa) generator and purified according to the previously published procedures using a DGA resin column from Eichrom Technologies LLC (Lisle, IL, USA) [22,23]. Radioactivity of 68 Ga-labeled peptides and peptidomimetics was measured using a Capintec (Ramsey, NJ, USA) CRC-25R/W dose calibrator.…”

Section: General Methodsmentioning

confidence: 99%

“…Purification of 68 Ga eluated from 68 Ge/ 68 Ga generator and labeling experiments were performed following our previously published procedures [22,23]. Purified 68 Ga in 0.5 mL of water was added into a 4-mL glass vial preloaded with 0.7 mL of HEPES buffer (2 M, pH 5.0) and 25 µg of the precursor.…”

Section: Synthesis Of 68 Ga-labeled Peptides and Peptidomimeticsmentioning

confidence: 99%

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Evaluation of Met-Val-Lys as a Renal Brush Border Enzyme-Cleavable Linker to Reduce Kidney Uptake of 68Ga-Labeled DOTA-Conjugated Peptides and Peptidomimetics

Bendre¹,

Zhang²,

Kuo³

et al. 2020

Molecules

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High kidney uptake is a common feature of peptide-based radiopharmaceuticals, leading to reduced detection sensitivity for lesions adjacent to kidneys and lower maximum tolerated therapeutic dose. In this study, we evaluated if the Met-Val-Lys (MVK) linker could be used to lower kidney uptake of 68Ga-labeled DOTA-conjugated peptides and peptidomimetics. A model compound, [68Ga]Ga-DOTA-AmBz-MVK(Ac)-OH (AmBz: aminomethylbenzoyl), and its derivative, [68Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH, coupled with the PSMA (prostate-specific membrane antigen)-targeting motif of the previously reported HTK01166 were synthesized and evaluated to determine if they could be recognized and cleaved by the renal brush border enzymes. Additionally, positron emission tomography (PET) imaging, ex vivo biodistribution and in vivo stability studies were conducted in mice to evaluate their pharmacokinetics. [68Ga]Ga-DOTA-AmBz-MVK(Ac)-OH was effectively cleaved specifically by neutral endopeptidase (NEP) of renal brush border enzymes at the Met-Val amide bond, and the radio-metabolite [68Ga]Ga-DOTA-AmBz-Met-OH was rapidly excreted via the renal pathway with minimal kidney retention. [68Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH retained its PSMA-targeting capability and was also cleaved by NEP, although less effectively when compared to [68Ga]Ga-DOTA-AmBz-MVK(Ac)-OH. The kidney uptake of [68Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH was 30% less compared to that of [68Ga]Ga-HTK01166. Our data demonstrated that derivatives of [68Ga]Ga-DOTA-AmBz-MVK-OH can be cleaved specifically by NEP, and therefore, MVK can be a promising cleavable linker for use to reduce kidney uptake of radiolabeled DOTA-conjugated peptides and peptidomimetics.

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Section: General Methodsmentioning

confidence: 99%

Section: Synthesis Of 68 Ga-labeled Peptides and Peptidomimeticsmentioning

confidence: 99%

Evaluation of Met-Val-Lys as a Renal Brush Border Enzyme-Cleavable Linker to Reduce Kidney Uptake of 68Ga-Labeled DOTA-Conjugated Peptides and Peptidomimetics

Bendre¹,

Zhang²,

Kuo³

et al. 2020

Molecules

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“…In 2012, our research group began developing B1R radiotracers for cancer imaging with PET [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. We synthesized three kallidin derivatives and appended the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator at N -terminus, separated by a 6-aminohexanoic acid (Ahx) or 9-amino-4,7-dioxanonanoic acid (dPEG2) linker [ 77 ].…”

Section: Imaging Of Kinin Receptorsmentioning

confidence: 99%

A Systematic Review of Molecular Imaging Agents Targeting Bradykinin B1 and B2 Receptors

Lau¹,

Rousseau²,

Kwon³

et al. 2020

Pharmaceuticals

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Kinins, bradykinin and kallidin are vasoactive peptides that signal through the bradykinin B1 and B2 receptors (B1R and B2R). B2R is constitutively expressed in healthy tissues and mediates responses such as vasodilation, fluid balance and retention, smooth muscle contraction, and algesia, while B1R is absent in normal tissues and is induced by tissue trauma or inflammation. B2R is activated by kinins, while B1R is activated by kinins that lack the C-terminal arginine residue. Perturbations of the kinin system have been implicated in inflammation, chronic pain, vasculopathy, neuropathy, obesity, diabetes, and cancer. In general, excess activation and signaling of the kinin system lead to a pro-inflammatory state. Depending on the disease context, agonism or antagonism of the bradykinin receptors have been considered as therapeutic options. In this review, we summarize molecular imaging agents targeting these G protein-coupled receptors, including optical and radioactive probes that have been used to interrogate B1R/B2R expression at the cellular and anatomical levels, respectively. Several of these preclinical agents, described herein, have the potential to guide therapeutic interventions for these receptors.

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“…3). DOTA and NODA are chelators of positron-emitting metal ions or metal-F complexes that are condensed with a spacer and with the antagonist B-9958 in the work of Zhang et al[66]. Following injection into tumor-bearing animals, positron emission tomography neatly identified the tumoral mass in a specific manner (i.e., labeling prevented by the co-treatment with an unlabeled ligand).…”

mentioning

confidence: 99%

“…3, Some of the second generation peptide antagonists possessing a constrained structure[9,98]. 4, N-terminal protection of Lys-[Leu 8 ]des-Arg 9 -BK conferring resistance to aminopeptidase Further modification the antagonist B-9958 with N-terminal extensions to confer aminopeptidase resistance[51,65], conjugation with a fluorophore of with an isotope-labeled moiety (the latter from Zhang et al,[66]). 6, N-terminal prolongation of Lys-des-Arg 9 -BK to obtain bifunctional agonist ligands[57,78].…”

mentioning

confidence: 99%

Bifunctional ligands of the bradykinin B 2 and B 1 receptors: An exercise in peptide hormone plasticity

et al. 2018

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Kinins are the small and fragile hydrophilic peptides related to bradykinin (BK) and derived from circulating kininogens via the action of kallikreins. Kinins bind to the preformed and widely distributed B receptor (BR) and to the inducible B receptor (BR). BRs and BRs are related G protein coupled receptors that possess natural agonist ligands of nanomolar affinity (BK and Lys BK for BRs, Lys-des-Arg-BK for BR). Decades of structure-activity exploration have resulted in the production of peptide analogs that are antagonists, one of which is clinically used (the BR antagonist icatibant), and also non-peptide ligands for both receptor subtypes. The modification of kinin receptor ligands has made them resistant to extracellular or endosomal peptidases and/or produced bifunctional ligands, defined as agonist or antagonist peptide ligands conjugated with a chemical fluorophore (emitting in the whole spectrum, from the infrared to the ultraviolet), a drug-like moiety, an epitope, an isotope chelator/carrier, a cleavable sequence (thus forming a pro-drug) and even a fused protein. Dual molecular targets for specific modified peptides may be a source of side effects or of medically exploitable benefits. Biotechnological protein ligands for either receptor subtype have been produced: they are enhanced green fluorescent protein or the engineered peroxidase APEX2 fused to an agonist kinin sequence at their C-terminal terminus. Antibodies endowed with pharmacological actions (agonist, antagonist) at BR have been reported, though not monoclonal antibodies. These findings define classes of alternative ligands of the kinin receptor of potential therapeutic and diagnostic value.

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Radiolabeled B9958 Derivatives for Imaging Bradykinin B1 Receptor Expression with Positron Emission Tomography: Effect of the Radiolabel–Chelator Complex on Biodistribution and Tumor Uptake

Cited by 14 publications

References 25 publications

Evaluation of Met-Val-Lys as a Renal Brush Border Enzyme-Cleavable Linker to Reduce Kidney Uptake of 68Ga-Labeled DOTA-Conjugated Peptides and Peptidomimetics

Evaluation of Met-Val-Lys as a Renal Brush Border Enzyme-Cleavable Linker to Reduce Kidney Uptake of 68Ga-Labeled DOTA-Conjugated Peptides and Peptidomimetics

A Systematic Review of Molecular Imaging Agents Targeting Bradykinin B1 and B2 Receptors

Bifunctional ligands of the bradykinin B 2 and B 1 receptors: An exercise in peptide hormone plasticity

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