Positron emission tomography of [18F]-big endothelin-1 reveals renal excretion but tissue-specific conversion to [18F]-endothelin-1 in lung and liver.
OBJECTIVE
Big endothelin-1 (ET-1) circulates in plasma but does not bind to ET receptors until converted to ET-1 by smooth muscle converting enzymes. We hypothesized that tissue-specific conversion of [(18)F]-big ET-1 to [(18)F]-ET-1 could be imaged dynamically in vivo within target organs as binding to ET receptors.


METHODS
[(18)F]-big ET-1 conversion imaged in vivo following infusion into rats using positron emission tomography (PET).


RESULTS
[(18)F]-big ET-1 was rapidly cleared from the circulation (t(1/2)= 2.9 +/- 0.1 min). Whole body microPET images showed highest uptake of radioactivity in three major organs. In lungs and liver, time activity curves peaked within 2.5 min, then plateaued reaching equilibrium after 10 min, with no further decrease after 120 min. Phosphoramidon did not alter half life of [(18)F]-big ET-1 but uptake was reduced in lung (42%) and liver (45%) after 120 min, consistent with inhibition of enzyme conversion and reduction of ET-1 receptor binding. The ET(A) antagonist, FR139317 did not alter half-life of [(18)F]-big ET-1 (t(1/2)= 2.5 min) but radioactivity was reduced in all tissues except for kidney consistent with reduction in binding to ET(A) receptors. In kidney, however, the peak in radioactivity was higher but time to maximum accumulation was slower ( approximately 30 min), which was increased by phosphoramidon, reflecting renal excretion with low conversion and binding to ET receptors.


CONCLUSIONS
A major site for conversion was within the vasculature of the lung and liver, whereas uptake in kidney was more complex, reflecting excretion of [(18)F]-big ET-1 without conversion to ET-1.
Johnström
Peter
P
Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Fryer
Tim D
TD
Richards
Hugh K
HK
Maguire
Janet J
JJ
Clark
John C
JC
Pickard
John D
JD
Davenport
Anthony P
AP
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001345:Autoradiography; D001381:Azepines / Q000494:pharmacology; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D000072396:Endothelin-Converting Enzymes; D004789:Enzyme Activation; D005462:Fluorine Radioisotopes; D006020:Glycopeptides / Q000494:pharmacology; D006207:Half-Life; D007211:Indoles / Q000494:pharmacology; D007262:Infusions, Intravenous; D007668:Kidney / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D057054:Molecular Imaging; D015336:Molecular Probe Techniques; D049268:Positron-Emission Tomography; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism; D014018:Tissue Distribution; D051598:Whole Body Imaging
D001381:Azepines; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D005462:Fluorine Radioisotopes; D006020:Glycopeptides; D007211:Indoles; D011480:Protease Inhibitors; D044022:Receptor, Endothelin A; C079574:FR 139317; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon
Br J Pharmacol. 2005 Jan;144(1):115-22
15644875
Eur J Biochem. 1993 Dec 1;218(2):493-8
8269939
Br J Pharmacol. 1999 Jan;126(2):391-8
10077230
Proc Natl Acad Sci U S A. 1988 Dec;85(24):9797-800
3059352
Br J Pharmacol. 1997 Dec;122(8):1687-93
9422815
Br J Pharmacol. 1995 Sep;116(2):1821-8
8528566
Clin Sci (Lond). 2002 Aug;103 Suppl 48:4S-8S
12193043
Br J Pharmacol. 1997 Dec;122(8):1647-54
9422810
Can J Physiol Pharmacol. 2002 May;80(5):440-9
12056551
Circ Res. 1996 Oct;79(4):794-801
8831503
Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):703-7
1992461
J Immunol Methods. 1990 Mar 9;127(2):165-70
2179411
Methods Mol Biol. 2005;306:155-72
15867468
Peptides. 1994;15(3):505-10
7937326
J Cardiovasc Pharmacol. 1989;13 Suppl 5:S5-7; discussion S18
2473327
J Cardiovasc Pharmacol. 1998;31 Suppl 1:S22-6
9595390
Comput Med Imaging Graph. 1989 Nov-Dec;13(6):433-54
2688869
Phys Med Biol. 2001 Jul;46(7):1845-62
11474929
Am J Physiol. 1991 Jul;261(1 Pt 2):R257-63
1650147
J Cardiovasc Pharmacol. 1991;17 Suppl 7:S503-5
1725425
Methods Mol Biol. 2005;306:217-32
15867471
Biochem Biophys Res Commun. 1988 Nov 15;156(3):1182-6
3056409
J Mol Endocrinol. 1998 Dec;21(3):307-15
9845671
Circulation. 1997 Jan 7;95(1):221-30
8994440
Handb Exp Pharmacol. 2006;(176 Pt 1):295-329
16999223
J Hepatol. 1996 Nov;25(5):700-6
8938548
J Cardiovasc Pharmacol. 1998;31 Suppl 1:S1-3
9595383
Br J Pharmacol. 2009 Nov;158 Suppl 1:S1-254
19883461
Am Heart J. 1998 Apr;135(4):614-20
9539476
Biochem Biophys Res Commun. 1991 Sep 16;179(2):1122-6
1898393
Biochem Biophys Res Commun. 1991 Oct 31;180(2):1019-23
1953706
Clin Sci (Lond). 1994 Aug;87(2):245-51
7924171
Br J Pharmacol. 1991 Aug;103(4):2009-15
1912989
Br J Pharmacol. 1998 Sep;125(2):238-40
9786493
J Cardiovasc Pharmacol. 1993;22 Suppl 8:S278-81
7509965
Eur J Nucl Med Mol Imaging. 2002 Jan;29(1):98-114
11807613
J Cardiovasc Pharmacol. 1991;17 Suppl 7:S506-8
1725426
Br J Pharmacol. 1993 Dec;110(4):1532-6
8306098
Circulation. 1996 Oct 1;94(7):1578-84
8840847
Eur J Cancer. 2002 Nov;38(16):2173-88
12387842
J Hypertens. 1998 Aug;16(8):1081-98
9794709
Curr Opin Investig Drugs. 2003 Sep;4(9):1076-81
14582451