Quantification of [11C]GB67 binding to cardiac α1-adrenoceptors with positron emission tomography: validation in pigs

  • So-Jin Park-Holohan
  • Marie-Claude Asselin
  • David R. Turton
  • Sharron L. Williams
  • Susan P. Hume
  • Paolo G. Camici
  • Ornella E. Rimoldi
Original Article



An increase in human cardiac α1-adrenoceptor (α1-AR) density is associated with various diseases such as myocardial ischemia, congestive heart failure, hypertrophic cardiomyopathy and hypertension. Positron emission tomography (PET) with an appropriate radioligand offers the possibility of imaging receptor function in the normal and diseased heart. [11C]GB67, an analogue of prazosin, has been shown in rats to have potential as a PET ligand with high selectivity to α1-AR. However, α1-AR density is up to ten times higher in rat heart compared to that in man. The aim of the present preclinical study was to extend the previous evaluation to a large mammal heart, where the α1-AR density is comparable to man, and to validate a method for quantification before PET studies in man.


Seven [11C]GB67 PET studies, with weight-adjusted target dose of either 5.29 MBq kg−1 (pilot, test–retest and baseline–predose studies) or 8.22 MBq kg−1 (baseline–displacement studies), were performed in four anaesthetised pigs (39.5 ± 3.9 kg). Total myocardial volume of distribution (V T) was estimated under different pharmacological conditions using compartmental analysis with a radiolabelled metabolite-corrected arterial plasma input function. A maximum possible blocking dose of 0.12 μmol kg−1 of unlabeled GB67 was given 20 min before [11C]GB67 administration in the predose study and 45 min after administration of [11C]GB67 in the displacement study. In addition, [15O]CO (3,000 MBq) and [15O]H2O, with weight adjusted target dose of 10.57 MBq kg−1, were also administered for estimation of blood volume recovery (RC) of the left ventricular cavity and myocardial perfusion (MBF), respectively.


[11C]GB67 V T values (in ml cm−3) were estimated to be 24.2 ± 5.5 (range, 17.3–31.3), 10.1 (predose) and 11.6 (displacement). MBF did not differ within each pig, including between baseline and predose conditions. Predose and displacement studies showed that specific binding of [11C]GB67 to myocardial α1-ARs accounts for approximately 50% of V T.


The present study offers a methodology for using [11C]GB67 as a radioligand to quantify human myocardial α1-ARs in clinical PET studies.


α1-Adrenoceptors [11C]GB67 Myocardium Pig Positron emission tomography (PET) 



The authors are grateful to the other members of Hammersmith Imanet for their interest and support, in particular Mr. Andy Blyth and Ms. Andreanna Williams for their help in PET data acquisition, Ms. Safiye Osman and her team for the blood analyses and Dr. Christopher Rhodes, Dr. Terence Spinks and Dr. Kris Thielemans for valuable discussions.


  1. 1.
    Molkentin JD, Dorn IG II. Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Ann Rev Physiol 2001;63:391–426.CrossRefGoogle Scholar
  2. 2.
    Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003;362 9377:7–13.PubMedCrossRefGoogle Scholar
  3. 3.
    Esposito G, Rapacciuolo A, Naga PS, Takaoka H, Thomas S, Koch W, et al. Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress. Circulation 2002;105 1:85–92.PubMedCrossRefGoogle Scholar
  4. 4.
    Wettschureck N, Rutten H, Zywietz A, Gehring D, Wilkie TM, Chen J, et al. Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Galphaq/Galpha11 in cardiomyocytes. Nat Med 2001;7 11:1236–40.PubMedCrossRefGoogle Scholar
  5. 5.
    Bishopric NH, Simpson PC, Ordahl CP. Induction of the skeletal alpha-actin gene in alpha 1-adrenoceptor-mediated hypertrophy of rat cardiac myocytes. J Clin Invest 1987;80 4:1194–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Ikeda U, Tsuruya Y, Yaginuma T. Alpha 1-adrenergic stimulation is coupled to cardiac myocyte hypertrophy. Am J Physiol 1991;260 3 Pt 2:H953–6.PubMedGoogle Scholar
  7. 7.
    Hwang KC, Gray CD, Sweet WE, Moravec CS, Im MJ. Alpha 1-adrenergic receptor coupling with Gh in the failing human heart. Circulation 1996;94 4:718–26.PubMedGoogle Scholar
  8. 8.
    Shan K, Bick RJ, Poindexter BJ, Nagueh SF, Shimoni S, Verani MS, et al. Altered adrenergic receptor density in myocardial hibernation in humans: a possible mechanism of depressed myocardial function. Circulation 2000;102 21:2599–606.PubMedGoogle Scholar
  9. 9.
    Steinfath M, Chen YY, Lavicky J, Magnussen O, Nose M, Rosswag S, et al. Cardiac alpha 1-adrenoceptor densities in different mammalian species. Br J Pharmacol 1992;107 1:185–8.PubMedGoogle Scholar
  10. 10.
    Delforge J, Syrota A, Lancon JP, Nakajima K, Loc’h C, Janier M, et al. Cardiac beta-adrenergic receptor density measured in vivo using PET, CGP 12177, and a new graphical method. J Nucl Med 1991;32 4:739–48.PubMedGoogle Scholar
  11. 11.
    Doze P, Elsinga PH, van Waarde A, Pieterman RM, Pruim J, Vaalburg W, et al. Quantification of beta-adrenoceptor density in the human heart with (S)-[11C]CGP 12388 and a tracer kinetic model. Eur J Nucl Med Mol Imaging 2002;29 3:295–304.PubMedCrossRefGoogle Scholar
  12. 12.
    Lefroy DC, de Silva R, Choudhury L, Uren NG, Crake T, Rhodes CG, et al. Diffuse reduction of myocardial beta-adrenoceptors in hypertrophic cardiomyopathy: a study with positron emission tomography. J Am Coll Cardiol 1993;22 6:1653–60.PubMedCrossRefGoogle Scholar
  13. 13.
    Giardina D, Brasili L, Gregori M, Massi M, Picchio MT, Quaglia W, et al. Structure–activity relationships in prazosin-related compounds. Effect of replacing a piperazine ring with an alkanediamine moiety on alpha 1-adrenoreceptor blocking activity. J Med Chem 1989;32 1:50–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Law MP, Osman S, Pike VW, Davenport RJ, Cunningham VJ, Rimoldi O, et al. Evaluation of [11C]GB67, a novel radioligand for imaging myocardial alpha 1-adrenoceptors with positron emission tomography. Eur J Nucl Med 2000;27 1:7–17.PubMedCrossRefGoogle Scholar
  15. 15.
    Yang M, Ruan J, Voller M, Schalken J, Michel MC. Differential regulation of human alpha1-adrenoceptor subtypes. Naunyn-Schmiedebergs Arch Pharmacol 1999;359 6:439–46.PubMedCrossRefGoogle Scholar
  16. 16.
    Wikberg-Matsson A, Wikberg JE, Uhlen S. Characterization of alpha1-adrenoceptor subtypes in the pig. Eur J Pharmacol 1998;347 2–3:301–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Davenport RJ, Pike VW, Law MP, Giardinà D. Radiosynthesis of 11C-GB67—a potential radioligand for the study of alpha1-adrenoceptors with PET. J Label Compd Radiopharm 1995;37:387–8.Google Scholar
  18. 18.
    Turton D, Hammersmith Imanet Limited. Preparation of 11C methyl iodide and of the radioligand 11C GB 67. Patent number WO-2006100481, 2006, UK.Google Scholar
  19. 19.
    Dinelle K, Thielemans K, Tsoumpas C, Spinks TJ. An evaluation of various analytic reconstruction algorithms and implementations for 2D and 3D PET. IEEE Nucl Sci Symp Conf Rec 2004;7:4043–7.CrossRefGoogle Scholar
  20. 20.
    Martin WR, Powers WJ, Raichle ME. Cerebral blood volume measured with inhaled C15O and positron emission tomography. J Cereb Blood Flow Metab 1987;7:421–6.PubMedGoogle Scholar
  21. 21.
    Ranicar ASO, Williams CW, Schnorr L, Clark JC, Rhodes CG, Bloomfield PM, et al. The on-line monitoring of continuously withdrawn arterial blood during PET studies using a single BGO/photomultiplier assembly and non-stick tubing. Med Prog Technol 1991;17:259–64.PubMedGoogle Scholar
  22. 22.
    Robb R. The biomedical imaging resource at Mayo Clinic [guest editorial]. IEEE Trans Med Imaging 2001;20:854–67.PubMedCrossRefGoogle Scholar
  23. 23.
    Hermansen F, Ashburner J, Spinks TJ, Kooner JS, Camici PG, Lammertsma AA. Generation of myocardial factor images directly from the dynamic oxygen-15-water scan without use of an oxygen-15-carbon monoxide blood-pool scan. J Nucl Med 1998;39 10:1696–702.PubMedGoogle Scholar
  24. 24.
    Koeppe RA, Holthoff VA, Frey KA, Kilbourn MR, Kuhl DE. Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography. J Cereb Blood Flow Metab 1991;11 5:735–44.PubMedGoogle Scholar
  25. 25.
    Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 2007;27 9:1533–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Schafers KP, Spinks TJ, Camici PG, Bloomfield PM, Rhodes CG, Law MP, et al. Absolute quantification of myocardial blood flow with H2 15O and 3-dimensional PET: an experimental validation. J Nucl Med 2002;43 8:1031–40.PubMedGoogle Scholar
  27. 27.
    Tsutsui H, Tomoike H, Nakamura M. Quantitative and autoradiographic analyses of alpha-adrenergic and serotonergic receptors on aorta and coronary artery. Am J Physiol 1990;259 5 Pt 2:H1343–50.PubMedGoogle Scholar
  28. 28.
    Delforge J, Mesangeau D, Dolle F, Merlet P, Loc’h C, Bottlaender M, et al. In vivo quantification and parametric images of the cardiac beta-adrenergic receptor density. J Nucl Med 2002;43 2:215–26.PubMedGoogle Scholar
  29. 29.
    Gillings NM, Bender D, Falborg L, Marthi K, Munk OL, Cuming P. Kinetics of the metabolism of four PET radioligands in living minipigs. Nucl Med Biol 2001;28:97–104.PubMedCrossRefGoogle Scholar
  30. 30.
    Price DT, Lefkowitz RJ, Caron MG, Berkowitz D, Schwinn DA. Localization of mRNA for three distinct alpha 1-adrenergic receptor subtypes in human tissues: implications for human alpha-adrenergic physiology. Mol Pharmacol 1994;45 2:171–5.PubMedGoogle Scholar
  31. 31.
    Matarrese M, Moresco RM, Romeo G, Turolla EA, Simonelli P, Todde S, et al. [11C]RN5: a new agent for the in vivo imaging of myocardial alpha1-adrenoceptors. Eur J Pharmacol 2002;453:231–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Hume SP, Gunn RN, Jones T. Pharmacological constraints associated with positron emission tomographic scanning of small laboratory animals. Eur J Nucl Med 1998;25:173–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • So-Jin Park-Holohan
    • 1
  • Marie-Claude Asselin
    • 1
    • 2
  • David R. Turton
    • 1
  • Sharron L. Williams
    • 3
  • Susan P. Hume
    • 1
  • Paolo G. Camici
    • 3
  • Ornella E. Rimoldi
    • 3
    • 4
  1. 1.Hammersmith Imanet Ltd., GE HealthCare, Cyclotron BuildingHammersmith HospitalLondonUK
  2. 2.Wolfson Molecular Imaging CentreThe University of ManchesterManchesterUK
  3. 3.MRC Clinical Sciences Centre, Cyclotron BuildingHammersmith HospitalLondonUK
  4. 4.Cardiovascular Research Institute Department of MedicineNew York Medical CollegeValhallaUSA

Personalised recommendations