PET-compatible endothelin receptor radioligands: Synthesis and first in vitro and in vivo studies

Carsten Höltke, Marilyn P. Law, Stefan Wagner, Klaus Kopka, Andreas Faust, Hans-Jörg Breyholz, Otmar Schober, Christoph Bremer, Burkhard Riemann, Michael Schäfers, Carsten Höltke, Marilyn P. Law, Stefan Wagner, Klaus Kopka, Andreas Faust, Hans-Jörg Breyholz, Otmar Schober, Christoph Bremer, Burkhard Riemann, Michael Schäfers

Index: Bioorg. Med. Chem. 17(20) , 7197-208, (2009)

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Abstract

The expression and function of endothelin (ET) receptors is abnormal in cardiovascular diseases, tumor progression, and tumor metastasis. In this study, we prepared two [(18)F]-fluorinated derivatives of the non-peptide ET(A) receptor antagonist PD 156707 and evaluated their ET receptor binding potencies. Ex vivo as well as in vivo biodistribution studies in mice were performed, as well as the metabolism of the radiotracer, which was examined by metabolite analysis in mice and rats. All tested derivatives of PD 156707 exhibited potent in vitro pharmacological characteristics with K(i) values comparable to that of the lead compound. The biodistribution studies showed a high accumulation of the tracer in bile and intestine. In vivo we were able to show that the visualization of the heart as a major target organ with high ET(A)R expression is possible.