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Amino Acids

, Volume 51, Issue 2, pp 219–244 | Cite as

Synthesis, 18F-labelling and radiopharmacological characterisation of the C-terminal 30mer of Clostridium perfringens enterotoxin as a potential claudin-targeting peptide

  • Reik LöserEmail author
  • Miriam Bader
  • Manuela Kuchar
  • Robert Wodtke
  • Jens Lenk
  • Johanna Wodtke
  • Konstantin Kuhne
  • Ralf Bergmann
  • Cathleen Haase-Kohn
  • Marie Urbanová
  • Jörg Steinbach
  • Jens Pietzsch
Original Article
  • 245 Downloads

Abstract

The cell surface receptor claudin-4 (Cld-4) is upregulated in various tumours and represents an important emerging target for both diagnosis and treatment of solid tumours of epithelial origin. The C-terminal fragment of the Clostridium perfringens enterotoxin cCPE290–319 appears as a suitable ligand for targeting Cld-4. The synthesis of this 30mer peptide was attempted via several approaches, which has revealed sequential SPPS using three pseudoproline dipeptide building blocks to be the most efficient one. Labelling with fluorine-18 was achieved on solid phase using N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) and 4-[18F]fluorobenzoyl chloride as 18F-acylating agents, which was the most advantageous when [18F]SFB was reacted with the resin-bound 30mer containing an N-terminal 6-aminohexanoic spacer. Binding to Cld-4 was demonstrated via surface plasmon resonance using a protein construct containing both extracellular loops of Cld-4. In addition, cell binding experiments were performed for 18F-labelled cCPE290–319 with the Cld-4 expressing tumour cell lines HT-29 and A431 that were complemented by fluorescence microscopy studies using the corresponding fluorescein isothiocyanate-conjugated peptide. The 30mer peptide proved to be sufficiently stable in blood plasma. Studying the in vivo behaviour of 18F-labelled cCPE290–319 in healthy mice and rats by dynamic PET imaging and radiometabolite analyses has revealed that the peptide is subject to substantial liver uptake and rapid metabolic degradation in vivo, which limits its suitability as imaging probe for tumour-associated Cld-4.

Keywords

Radiolabelled peptides 18F-fluorobenzoylation Difficult peptide sequences Claudin family of tight junction proteins Molecular imaging Small animal positron emission tomography 

Abbreviations

Ac

Acetyl

Ahx

6-Aminohexanoyl

BSA

Bovine serum albumin

Cld

Claudin

2-ClTrtCl

2-Chlorotrityl chloride

CPE

Clostridium perfringens enterotoxin

cCPE

C-terminal domain of Clostridium perfringens enterotoxin

DMEM

Dulbecco’s modified Eagle’s medium

DIPEA

N,N-Diisopropylamine

DMF

N,N-Dimethylformamide

DMSO

Dimethyl sulfoxide

EC

Electron capture

ECD

Electronic circular dichroism

EDTA

N,N,N′,N′-Ethylenediamine tetraacetic acids

ESI

Electrospray ionisation

ESM

Electronic supplementary material

Et

Ethyl

FBz

4-Fluorobenzoyl

FITC

Fluorescein-5-isothiocyanate

Fmoc

9H‐Fluorene-9-ylmethoxycarbonyl

HFIP

Hexafluoroisopropanol

HATU

O-(7-Azabenzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium hexafluorophosphate

HBTU

O-(Benzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium hexafluorophosphate

HOBt

1-Hydroxybenzotriazol

HPLC

High performance liquid chromatography

ID

Injected dose

MBHA

4‐Methyl benzhydrylamine

Me

Methyl

MR

Magnetic resonance

MS

Mass spectrometry

PBS

Phosphate-buffered saline

PDA

Photodiode array

PET

Positron emission tomography

PFA

Paraformaldeyde

p.i.

Post injectionem

RIPA

Radioimmunoprecipitation assay

RP

Reversed phase

SDS-PAGE

Sodium dodecyl sulphate polyacrylamide gel electrophoresis

[18F]SFB

N-Succinimidyl 4-[18F]fluorobenzoate

SPECT

Single photon emission computed tomography

SPR

Surface plasmon resonance

SPPS

Solid-phase peptide synthesis

TBS

Tris-buffered saline

tBu

tert-Butyl

TFA

Trifluoroacetic acid

TFE

2,2,2-Trifluoroethanol

Trt

Trityl

UPLC

Ultra performance liquid chromatography

Notes

Acknowledgements

We wish to thank Peggy Nehring and Uta Lenkeit for assisting in peptide and radiochemical synthesis and Stefan Preusche and the cyclotron team for providing [18F]fluoride. We highly appreciate the support of Catharina Knöfel, Aline Morgenegg and Mareike Barth in the cell-based and immunohistochemical experiments. Furthermore, we are grateful to Andrea Suhr and Regina Herrlich for skilful assistance in the animal experiments. RL is grateful for partial financial support by the Fonds der Chemischen Industrie. The authors thank the Helmholtz Association for funding a part of this work through the Helmholtz Cross-Programme Initiative “Technology and Medicine—Adaptive Systems”.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to declare.

Ethical approval

The animal experiments were performed in accordance to the guidelines of the German Regulations of Animal Welfare. The protocol was approved by the local Ethical Committee for Animal Experiments (Reference Numbers 24D-9168.11-4/2007-2 and 24-9168.21-4/2004-1).

Supplementary material

726_2018_2657_MOESM1_ESM.pdf (1.9 mb)
Supplementary material 1 (PDF 1924 kb)

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Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  • Reik Löser
    • 1
    • 2
    Email author
  • Miriam Bader
    • 1
    • 2
  • Manuela Kuchar
    • 1
    • 2
  • Robert Wodtke
    • 1
    • 2
  • Jens Lenk
    • 1
    • 2
  • Johanna Wodtke
    • 1
  • Konstantin Kuhne
    • 1
    • 2
  • Ralf Bergmann
    • 1
  • Cathleen Haase-Kohn
    • 1
  • Marie Urbanová
    • 3
  • Jörg Steinbach
    • 1
    • 2
  • Jens Pietzsch
    • 1
    • 2
  1. 1.Institute of Radiopharmaceutical Cancer ResearchHelmholtz-Zentrum Dresden RossendorfDresdenGermany
  2. 2.Faculty of Chemistry and Food Chemistry, School of ScienceTechnische Universität DresdenDresdenGermany
  3. 3.Department of Physics and MeasurementsUniversity of Chemistry and TechnologyPragueCzech Republic

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