Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats

Ralf Bergmann, Manja Kubeil, Kristof Zarschler, Sandeep Chhabra, Rajeev Babu Tajhya, Christine Beeton, Michael William Pennington, Michael H. Bachmann, Raymond S. Norton, Holger Stephan

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The peptide HsTX1[R14A] is a potent and selective blocker of the voltage-gated potassium channel Kv1.3, which is a highly promising target for the treatment of autoimmune diseases and other conditions. In order to assess the biodistribution of this peptide, it was conjugated with NOTA and radiolabelled with copper-64. [64Cu]Cu-NOTA-HsTX1[R14A] was synthesised in high radiochemical purity and yield. The radiotracer was evaluated in vitro and in vivo. The biodistribution and PET studies after intravenous and subcutaneous injections showed similar patterns and kinetics. The hydrophilic peptide was rapidly distributed, showed low accumulation in most of the organs and tissues, and demonstrated high molecular stability in vitro and in vivo. The most prominent accumulation occurred in the epiphyseal plates of trabecular bones. The high stability and bioavailability, low normal-tissue uptake of [64Cu]Cu-NOTA-HsTX1[R14A], and accumulation in regions of up-regulated Kv channels both in vitro and in vivo demonstrate that HsTX1[R14A] represents a valuable lead for conditions treatable by blockade of the voltage-gated potassium channel Kv1.3. The pharmacokinetics shows that both intravenous and subcutaneous applications are viable routes for the delivery of this potent peptide.

Original languageEnglish
Article number3756
Number of pages11
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 1 Dec 2017

Cite this

Bergmann, R., Kubeil, M., Zarschler, K., Chhabra, S., Tajhya, R. B., Beeton, C., ... Stephan, H. (2017). Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats. Scientific Reports, 7(1), [3756]. https://doi.org/10.1038/s41598-017-03998-x
Bergmann, Ralf ; Kubeil, Manja ; Zarschler, Kristof ; Chhabra, Sandeep ; Tajhya, Rajeev Babu ; Beeton, Christine ; Pennington, Michael William ; Bachmann, Michael H. ; Norton, Raymond S. ; Stephan, Holger. / Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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abstract = "The peptide HsTX1[R14A] is a potent and selective blocker of the voltage-gated potassium channel Kv1.3, which is a highly promising target for the treatment of autoimmune diseases and other conditions. In order to assess the biodistribution of this peptide, it was conjugated with NOTA and radiolabelled with copper-64. [64Cu]Cu-NOTA-HsTX1[R14A] was synthesised in high radiochemical purity and yield. The radiotracer was evaluated in vitro and in vivo. The biodistribution and PET studies after intravenous and subcutaneous injections showed similar patterns and kinetics. The hydrophilic peptide was rapidly distributed, showed low accumulation in most of the organs and tissues, and demonstrated high molecular stability in vitro and in vivo. The most prominent accumulation occurred in the epiphyseal plates of trabecular bones. The high stability and bioavailability, low normal-tissue uptake of [64Cu]Cu-NOTA-HsTX1[R14A], and accumulation in regions of up-regulated Kv channels both in vitro and in vivo demonstrate that HsTX1[R14A] represents a valuable lead for conditions treatable by blockade of the voltage-gated potassium channel Kv1.3. The pharmacokinetics shows that both intravenous and subcutaneous applications are viable routes for the delivery of this potent peptide.",
author = "Ralf Bergmann and Manja Kubeil and Kristof Zarschler and Sandeep Chhabra and Tajhya, {Rajeev Babu} and Christine Beeton and Pennington, {Michael William} and Bachmann, {Michael H.} and Norton, {Raymond S.} and Holger Stephan",
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Bergmann, R, Kubeil, M, Zarschler, K, Chhabra, S, Tajhya, RB, Beeton, C, Pennington, MW, Bachmann, MH, Norton, RS & Stephan, H 2017, 'Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats' Scientific Reports, vol. 7, no. 1, 3756. https://doi.org/10.1038/s41598-017-03998-x

Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats. / Bergmann, Ralf; Kubeil, Manja; Zarschler, Kristof; Chhabra, Sandeep; Tajhya, Rajeev Babu; Beeton, Christine; Pennington, Michael William; Bachmann, Michael H.; Norton, Raymond S.; Stephan, Holger.

In: Scientific Reports, Vol. 7, No. 1, 3756, 01.12.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats

AU - Bergmann, Ralf

AU - Kubeil, Manja

AU - Zarschler, Kristof

AU - Chhabra, Sandeep

AU - Tajhya, Rajeev Babu

AU - Beeton, Christine

AU - Pennington, Michael William

AU - Bachmann, Michael H.

AU - Norton, Raymond S.

AU - Stephan, Holger

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N2 - The peptide HsTX1[R14A] is a potent and selective blocker of the voltage-gated potassium channel Kv1.3, which is a highly promising target for the treatment of autoimmune diseases and other conditions. In order to assess the biodistribution of this peptide, it was conjugated with NOTA and radiolabelled with copper-64. [64Cu]Cu-NOTA-HsTX1[R14A] was synthesised in high radiochemical purity and yield. The radiotracer was evaluated in vitro and in vivo. The biodistribution and PET studies after intravenous and subcutaneous injections showed similar patterns and kinetics. The hydrophilic peptide was rapidly distributed, showed low accumulation in most of the organs and tissues, and demonstrated high molecular stability in vitro and in vivo. The most prominent accumulation occurred in the epiphyseal plates of trabecular bones. The high stability and bioavailability, low normal-tissue uptake of [64Cu]Cu-NOTA-HsTX1[R14A], and accumulation in regions of up-regulated Kv channels both in vitro and in vivo demonstrate that HsTX1[R14A] represents a valuable lead for conditions treatable by blockade of the voltage-gated potassium channel Kv1.3. The pharmacokinetics shows that both intravenous and subcutaneous applications are viable routes for the delivery of this potent peptide.

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U2 - 10.1038/s41598-017-03998-x

DO - 10.1038/s41598-017-03998-x

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