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Development and evaluation of endothelin-A receptor (radio)ligands for positron emission tomography

Kristin Michel1, Katrin Büther, Marilyn P Law

  • 1Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Strasse 33, D-48149 Münster, Germany. kristin.michel@uni-muenster.de

Journal of Medicinal Chemistry
|February 1, 2011
PubMed

Insights

Researchers developed new, more hydrophilic PET radioligands targeting endothelin (ET) receptors, improving imaging for cardiovascular diseases and tumors by reducing unwanted accumulation in the body.

Area of Science:

  • Radiochemistry
  • Molecular Imaging
  • Pharmacology

Background:

  • Endothelin (ET) receptors are implicated in cardiovascular diseases and cancer progression.
  • Previous ET(A) receptor radioligands showed high lipophilicity, leading to undesirable accumulation in bile and intestines.
  • There is a need for improved radioligands with better pharmacokinetic properties for diagnostic imaging.

Purpose of the Study:

  • To synthesize and evaluate novel, hydrophilic fluorinated derivatives of a non-peptide ET(A) receptor antagonist.
  • To develop improved positron emission tomography (PET) radioligands for visualizing ET(A) receptor expression.
  • To enhance diagnostic capabilities for diseases involving ET receptor abnormalities.

Main Methods:

  • Synthesis of a series of fluorinated ET(A) receptor antagonist derivatives.
  • In vitro evaluation of ligand affinity and subtype selectivity (ET(A) vs. ET(B)).
  • Radiosynthesis of [(18)F]17 and assessment of its stability in human serum.
  • In vivo biodistribution studies and small animal PET imaging to evaluate clearance and target uptake.

Main Results:

  • All synthesized compounds demonstrated high affinity for the ET(A) receptor (K(i) = 1.4-7.9 nM) and high selectivity over the ET(B) receptor.
  • The radioligand [(18)F]17 exhibited increased hydrophilicity and excellent stability in human serum.
  • Biodistribution and PET imaging confirmed improved clearance and specific uptake in target organs for [(18)F]17.

Conclusions:

  • Novel fluorinated derivatives represent promising candidates for PET imaging of ET(A) receptors.
  • [(18)F]17 offers improved hydrophilicity and pharmacokinetic properties compared to previous radioligands.
  • These findings support the potential of [(18)F]17 for enhanced diagnostic imaging in relevant diseases.

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