HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Johnström, P. Articles by Davenport, A. P. Search for Related Content PubMed PubMed Citation Articles by Johnström, P. Articles by Davenport, A. P.

---

BASIC BIOLOGY

Imaging Endothelin ET_B Receptors Using [¹⁸F]-BQ3020: In Vitro Characterization and Positron Emission Tomography (MicroPET)

Peter Johnström^*,1, James H. F. Rudd, Hugh K. Richards, Tim D. Fryer, John C. Clark, Peter L. Weissberg, John D. Pickard^, and Anthony P. Davenport^*

^* Clinical Pharmacology Unit, Division of Cardiovascular Medicine, Academic Neurosurgery, and Wolfson Brain Imaging Centre, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom

To whom requests for reprints should be addressed at ¹ Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Centre for Clinical Investigation, Level 6, Box 110, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom. E-mail: pjj20{at}medschl.cam.ac.uk

Abstract

The endothelin (ET) receptor system has been shown to play a role in a number of vascular diseases. We have synthesized ¹⁸F-and ¹¹C-labeled radioligands to enable in vivo imaging of the fundamental processes involved in ET receptor pharmacology in normal and diseased tissue using positron emission tomography (PET). One aim is to elucidate the proposed role of the ET_B subtype as clearing receptor, removing ET-1 from the circulation, and whether this is an important mechanism to limit the detrimental effects caused by upregulated ET-1 in disease. To image ET_B receptors we have labeled the selective agonist BQ3020 with ¹⁸F. In vitro characterization verified that [¹⁸F]-BQ3020 bound with a single subnanomolar affinity (K_D == 0.34 ± 0.10 nM, B_max == 9.23 ± 3.70 fmol/mg protein) to human left ventricle. Binding of [¹⁸F]-BQ3020 to human kidney was inhibited by ET-1 and unlabeled BQ3020 but not by the ET_A selective antagonist FR139317, confirming that selectivity for the ET_B receptor was retained. In vitro autoradiography revealed, as expected, high levels of ET_B receptor densities in lung and kidney medulla, whereas kidney cortex and heart showed lower levels of ET_B receptor densities. Furthermore, a high level of [¹⁸F]-BQ3020 binding was found to colocalize to macrophages in atherosclerotic coronary arteries. MicroPET studies demonstrated high uptake of [¹⁸F]-BQ3020 in ET_B receptor–rich tissue, including lung, liver and kidney. The in vivo biodistribution of [¹⁸F]-BQ3020 was comparable to that previously obtained for [¹⁸F]-ET-1, supporting our hypothesis that the ET_B receptor plays a significant role in the uptake of ET-1. In conclusion, [¹⁸F]-BQ3020 has retained high affinity and selectivity, allowing imaging of ET_B receptor distributions in vitro and in vivo in human and animal tissue. Furthermore, in vitro data suggest that [¹⁸F]-BQ3020 potentially can be used to image atherosclerotic lesions in vivo using PET.

Key Words: endothelin • ET_B receptors • positron emission tomography • microPET • ¹⁸F • in vivo imaging

This article has been cited by other articles:

				W. B. Mathews, N. Murugesan, J. Xia, U. Scheffel, J. Hilton, H. T. Ravert, R. F. Dannals, and Z. Szabo Synthesis and In Vivo Evaluation of Novel PET Radioligands for Imaging the Endothelin-A Receptor J. Nucl. Med., September 1, 2008; 49(9): 1529 - 1536. [Abstract] [Full Text] [PDF]

				M. P. S. Dunphy, H. Schoder, and H. W. Strauss Radionuclide Techniques for Identifying Vulnerable Plaque J. Nucl. Med., November 1, 2007; 48(11): 1753 - 1755. [Full Text] [PDF]