Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 4 947
of 0.7 mm (fwhm) in the transaxial and axial directions when
using an iterative resolution recovery reconstruction algorithm.
Subsequently, the scanning bed was transferred to the computed
tomography (CT) scanner (Inveon, Siemens Medical Solutions,
U.S.) and a CT acquisition with a spatial resolution of 29 μm
was performed for each mouse. Reconstructed image data sets
were co-registered using extrinsic markers attached to the multi-
modal scanning bed and the image analysis software (Inveon
Research Workplace 3.0, Siemens Medical Solutions, U.S.). On
the basis of the CT data, three-dimensional volumes of interest
(VOIs) were defined over the respective organs, transferred to
the co-registered PET data, and analyzed quantitatively.
(14) Bagnato, A.; Salani, D.; Di Castro, V.; Wu-Wong, J. R.; Tecce, R.;
Nicotra, M. R.; Venuti, A.; Natali, P. G. Expression of endothelin 1
and endothelin A receptor in ovarian carcinoma: evidence for an
autocrine role in tumor growth. Cancer Res. 1999, 59, 720–727.
(15) Nelson, J. B.; Chan-Tack, K.; Hedican, S. P.; Magnuson, S. R.;
Opgenorth, T. J.; Bova, G. S.; Simons, J. W. Endothelin-1 produc-
tion and decreased endothelin B receptor expression in advanced
prostate cancer. Cancer Res. 1996, 56, 663–668.
(16) Alanen, K.; Deng, D. X.; Chakrabarti, S. Augmented expression of
endothelin-1, endothelin-3 and the endothelin-B receptor in breast
carcinoma. Histopathology 2000, 36, 161–167.
€
€
(17) Wulfing, P.; Diallo, R.; Kersting, C.; Wulfing, C.; Poremba, C.;
Rody, A.; Greb, R. R.; Boecker, W.; Kiesel, L. Expression of
endothelin-1, endothelin-A, and endothelin-B receptor in human
breast cancer and correlation with long-term follow-up. Clin.
Cancer Res. 2003, 9, 4125–4131.
radioactivity ðcpsÞ=mL in the VOI
% ID mL- 1
¼
ꢀ 100
(18) Rosano, L.; Varmi, M.; Salani, D.; Di Castro, V.; Spinella, F.;
Natali, P. G.; Bagnato, A. Endothelin-1 induces tumor proteinase
activation and invasiveness of ovarian carcinoma cells. Cancer Res.
2001, 61, 8340–8346.
3
radioactivity ðcpsÞ mouse
Acknowledgment. The authors thank Anne Kanzog, Chris-
(19) Salani, D.;DiCastro, V.;Nicotra, M. R.;Rosano, L.;Tecce, R.;Venuti,
A.; Natali, P. G.; Bagnato, A. Role of endothelin-1 in neovascularization
of ovarian carcinoma. Am. J. Pathol. 2000, 157, 1537–1547.
(20) Del Bufalo, D.; Di Castro, V.; Biroccio, A.; Varmi, M.; Salani, D.;
Rosano, L.; Trisciuoglio, D.; Spinella, F.; Bagnato, A. Endothelin-
1 protects ovarian carcinoma cells against paclitaxel induced
apoptosis: requirement for Akt activation. Mol. Pharmacol. 2002,
61, 524–532.
€
tine Batza, Roman Priebe, and Claudia Graf for technical
support and the staff members of the Organic Chemistry
€
Institute, University of Munster, Germany, for spectroscopic
and analytical investigations. K.M. thanks Daniela Schrigten
€
for synthesizing and providing compounds 18 and 27. This
€
study was supported by the Bundesministerium fur Bildung
(21) Eberl, L. P.; Egidy, G.; Pinet, F.; Juillerat-Jeanneret, L. Endothelin
receptor blockade potentiates FasL-induced apoptosis in colon
carcinoma cells via the protein kinase C-pathway. J. Cardiovasc.
Pharmacol. 2000, 36, S354–356.
und Forschung (BMBF), Germany (MoBiMed Subproject
01EZ0809), and the Deutsche Forschungsgemeinschaft (DFG),
Germany (Grants SCHA 758/5-1 and SFB 656 A1/C6/Z5).
(22) Ali, H.; Dashwood, M.; Dawas, K.; Loizidou, M.; Savage, F.;
Taylor, I. Endothelin receptor expression in colorectal cancer.
J. Cardiovasc. Pharmacol. 2000, 36, S69–71.
(23) Winn, M.; Boyd, S. A.; Hutchins, C. W.; Jae, H.-S.; Tasker, A. S.;
Vongeldern, T. W.; Kester, J. A.; Sorensen, B. K. Preparation of
Pyrrolidinecarboxylic Acid Derivatives and Analogs as Endothelin
Antagonists. WO 9606095 A1 19960229, Feb 29, 1996; Abbott
Laboratories, U.S.
Supporting Information Available: Experimental procedures
and analytical data for compounds 10a, 10c, 10d, 12, 13, 15, and
22 and 1H, 13C, and 19F NMR data of compounds 19 and 23-
26. This material is available free of charge via the Internet at
(24) Bagnato, A.; Cirilli, A.; Salani, D.; Simeone, P.; Muller, A.;
Nicotra, M. R.; Natali, P. G.; Venuti, A. Growth inhibition of
cervix carcinoma cells in vivo by endothelin A receptor blockade.
Cancer Res. 2002, 62, 6381–6384.
(25) Rosano, L.; Spinella, F.; Salani, D.; Di Castro, V.; Venuti, A.;
Nicotra, M. R.; Natali, P. G.; Bagnato, A. Therapeutic targeting of
the endothelin A receptor in human ovarian carcinoma. Cancer
Res. 2003, 63, 2447–2453.
(26) Carducci, M. A.; Nelson, J. B.; Bowling, M. K.; Rogers, T.;
Eisenberger, M. A.; Sinibaldi, V.; Donehower, R.; Leahy, T. L.;
Carr, R. A.; Isaacson, J. D.; Janus, T. J.; Andre, A.; Hosmane,
B. S.; Padley, R. J. Atrasentan, an endothelin-receptor antagonist
for refractory adenocarcinomas: safety and pharmacokinetics.
J. Clin. Oncol. 2002, 20, 2171–2180.
References
(1) Henry, P. J. Endothelin receptor distribution and function in the
airways. Clin. Exp. Pharamacol. Physiol. 1999, 26, 162–167.
(2) Barton, M.; Yanagisawa, M. Endothelin: 20 years from discovery
to therapy. Can. J. Physiol. Pharmacol. 2006, 17, 485–492.
(3) Dhaun, N.; Goddard, J.; Webb, D. J. The endothelin system and its
antagonism in chronic kidney disease. J. Am. Soc. Nephrol. 2006,
17, 943–955.
(4) Giaid, A.; Yanagisawa, M.; Langleben, D.; Michel, R. P.; Levy, R.;
Shennib, H.; Kimura, S.; Masaki, T.; Duguid, W. P.; Stewart, D. J.
Expression of endothelin-1 in the lungs of patients with pulmonary
hypertension. N. Engl. J. Med. 1993, 328, 1732–1739.
(27) Carducci, M. A.; Padley, R. J.; Breul, J.; Vogelzang, N. J.; Zonnenberg,
B. A.; Daliani, D. D.; Schulman, C. C.; Nabulsi, A. A.;
Humerickhouse, R. A.; Weinberg, M. A.; Schmitt, J. L.; Nelson,
J. B. Effect of endothelin-A receptor blockade with atrasentan
on tumor progression in men with hormone-refractory prostate
cancer: a randomized, phase II, placebo-controlled trial. J. Clin.
Oncol. 2003, 21, 679–689.
(5) Pittman, Q. J. Endothelin, an emerging role in proinflammatory
pathways in brain. Am. J. Physiol.: Regul. Integr. Comp. Physiol.
2006, 290, R162–R163.
(6) Plusczyk, T.; Witzel, B.; Menger, M. D.; Schilling, M. ETA and
ETB receptor function in pancreatitis-associated microcirculatory
failure, inflammation, and parenchymal injury. Am. J. Physiol.:
Gastrointest. Liver Physiol. 2003, 285, G145–G153.
(28) Mathews, W. B.; Zober, T. G.; Ravert, H. T.; Scheffel, U.; Hilton,
J.; Sleep, D.; Dannals, R. F.; Szabo, Z. Synthesis and in vivo
evaluation of a PET radioligand for imaging the endothelin-A
receptor. Nucl. Med. Biol. 2006, 33, 15–19.
(7) Saito, Y.; Nakao, K.; Mukoyama, M.; Imura, H. Increased plasma
endothelin level in patients with essential hypertension. N. Engl. J.
Med. 1990, 322, 205.
(8) Teerlink, J. R.; Loffler, B. M.; Hess, P.; Maire, J. P.; Clozel, M.;
Clozel, J. P. Role of endothelin in the maintenance of blood
pressure in conscious rats with chronic heart failure. Acute effects
of the endothelin receptor antagonist Ro 47-0203 (bosentan).
Circulation 1994, 90, 2510–2518.
(29) Aleksic, S.; Szabo, Z.; Scheffel, U.; Ravert, H. T.; Mathews, W. B.;
Kerenyi, L.; Rauseo, P. A.; Gibson, R. E.; Burns, H. D.; Dannals,
R. F. In vivo labeling of endothelin receptors with [(11)C]L-753,037:
studies in mice and a dog. J. Nucl. Med. 2001, 42, 1274–1280.
(30) Johnstrøm, P.; Fryer, T. D.; Richards, H. K.; Barret, O.; Clark,
J. C.; Ohlstein, E. H.; Pickard, J. D.; Davenport, A. P. In vivo
imaging of cardiovascular endothelin receptors using the novel
radiolabelled antagonist [18F]-SB209670 and positron emission
tomography (microPET). J. Cardiovasc. Pharmacol. 2004, 44,
S34–S38.
(9) Nelson, J.; Bagnato, A.; Battistini, B.; Nisen, P. The endothelin
axis: emerging role in cancer. Nat. Rev. Cancer 2003, 3, 110–116.
(10) Bagnato, A.; Natali, P. G. Targeting endothelin axis in cancer.
Cancer Treat. Res. 2004, 119, 293–314.
ꢀ
(11) Bagnato, A.; Rosano, L. The endothelin axis in cancer. Int. J.
Biochem. Cell Biol. 2008, 40, 1443–1451.
ꢀ
(12) Bagnato, A.; Spinella, F.; Rosano, L. The endothelin axis in cancer:
the promise and the challenges of molecularly targeted therapy.
(31) Berryman, K. A.; Doherty, A. M.; Edmunds, J. J.; Patt, W. C.;
Plummer, M. S.; Repine, J. T. Preparation of 2(5H)-Furanones,
2(5H)-Thiophenones, 2(5H)-Pyrrolones and Benzodioxolyls as
Endothelin Antagonists. WO 9505376 A1 19950223, Feb 23,
1995; Warner Lambert Co., U.S.
Can. J. Physiol. Pharmacol. 2008, 86, 473–484.
(13) Asham, E.; Shankar, A.; Loizidou, M.; Fredericks, S.; Miller, K.;
Boulos, P. B.; Burnstock, G.; Taylor, I. Increased endothelin-1 in
colorectal cancer and reduction of tumour growth by ET(A)
receptor antagonism. Br. J. Cancer 2001, 85, 1759–1763.
(32) Doherty, A. M.; Patt, W. C.; Edmunds, J. J.; Berryman, K. A.;
Reisdorph, B. R.; Plummer, M. S.; Shahripour, A.; Lee, C.; Cheng,