Studies of cardiac receptors by positron emission tomography

  • Aren van Waarde
  • Paul K. Blanksma
  • Joan G. Meeder
  • Gerben M. Visser
  • Wiek H. van Gilst
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 133)


New concepts regarding neurohumoral regulation of cardiac function by myocardial receptors in health and disease have become prominent during the last two decades. Radioligand binding studies have greatly advanced our knowledge of hormone and neurotransmitter binding sites. Changes in the number and/or affinity of cardiac receptors have been assessed by in vitro techniques and shown to be associated with congestive heart failure [1, 2, 3], myocardial ischemia and infarction [4, 5, 6, 7, 8, 9], cardiomyopathy [10,11], hypertension [12,13], chronic drug administration [14, 15, 16, 17] and ageing [18]. In vivo assays may improve our understanding of the time course of diseases and enable better prognosis.


Positron Emission Tomography Positron Emission Tomography Study Label Compound Muscarinic Cholinergic Receptor Positron Emission Tomography Camera 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bristow MR, Minobe W, Rasmussen R, Hershberger RE, Hoffman BB. Alpha-1 adrenergic receptors in the nonfailing and failing human heart. J Pharmacol Exp Ther 1988; 247: 1039–45.PubMedGoogle Scholar
  2. 2.
    Bristow MR, Ginsburg R, Umans V et al. β1 and β2-adrenergic subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective β2 receptor downregulation in heart failure. Circ Res 1986; 59: 297–309.PubMedCrossRefGoogle Scholar
  3. 3.
    Brodde OE, Zerkowski HR, Borst HG, Maier W, Michel MC. Drug-and disease-induced changes of human cardiac β1 and β2 adrenoreceptors. Eur Heart J 1989; 10 (Suppl B): 38–44.Google Scholar
  4. 4.
    Mukherjee A, Bush LR, McCoy KE et al. Relationship between beta-adrenergic receptor numbers and physiological responses during experimental canine myocardial ischemia. Circ Res 1982; 50: 735–41.PubMedCrossRefGoogle Scholar
  5. 5.
    Maisel AS, Motulsky HJ, Insel PA. Externalization of beta-adrenergic receptors promoted by myocardial ischemia. Science 1985; 230: 183–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Strasser RH, Krimmer J, Marquetant R. Regulation of beta-adrenergic receptors: impaired desensitization in myocardial ischemia. J Cardiovasc Pharmacol 1988; 12: S15–S24.PubMedCrossRefGoogle Scholar
  7. 7.
    Mukherjee A, Wong TM, Buja LM et al. Beta-adrenergic and muscarinic cholinergic receptors in canine myocardium. Effects of ischemia. J Clin Invest 1979; 64: 1423–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Ohyanagi M, Matsumori Y, Iwasaki T. Beta-adrenergic receptors in ischemic and nonischemic canine myocardium: relation to ventricular fibrillation and effects of pretreatment with propranolol and hexamethonium. J Cardiovasc Pharmacol 1988; 11: 107–14.PubMedCrossRefGoogle Scholar
  9. 9.
    Freissmuth M, Schutz W, Weindlmayer-Gottel N et al. Effects of ischemia on the canine myocardial beta-adrenoreceptor-linked adenylate cyclase system. J Cardiovasc Pharmacol 1987; 10: 568–74.PubMedCrossRefGoogle Scholar
  10. 10.
    Amorim DS, Heer K, Jenner D et al. Is there autonomic impairment in congestive (dilated) cardiomyopathy? Lancet 1981; 1: 525–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Amorim DS, Olsen EGJ. Assessment of heart neurons in dilated (congestive) cardiomyopathy. Br Heart J 1982; 47: 11–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Yamada S, Ishima T, Tomita T, Hayashi T, Okada T, Hayashi E. Alterations in cardiac alpha-and beta-adrenoreceptors during the development of spontaneous hypertension. J Pharmacol Exp Ther 1984; 228: 454–9.PubMedGoogle Scholar
  13. 13.
    Hurwitz ML, Rosendorff C. Cardiovascular adrenoreceptor number and function in experimental hypertension in the baboon. J Cardiovasc Pharmacol 1985; 7(Suppl 6): S172–7.CrossRefGoogle Scholar
  14. 14.
    Kenakin TP, Beek D. In vitro studies on the cardiac activity of prenalterol with reference to its use in congestive heart failure. J Pharmacol Exp Ther 1982; 220: 77–85.PubMedGoogle Scholar
  15. 15.
    Gengo P, Skattebol A, Moran JF, Gallant S, Hawthorn M, Triggle DJ. Regulation by chronic drug administration of neuronal and cardiac calcium channel, beta-adrenoreceptor and muscarinic receptor levels. Biochem Pharmacol 1988; 37: 627–33.PubMedCrossRefGoogle Scholar
  16. 16.
    Golf S, Hansson V. Effects of beta blocking agents on the density of beta-adrenoreceptors and adenylate cyclase response in human myocardium: intrinsic sympathomimetic activity favours receptor regulation. Cardiovasc Res 1986; 20: 637–44.PubMedCrossRefGoogle Scholar
  17. 17.
    van den Meiracker AH, in’tVeld AJ, Boomsma F, Fischberg DJ, Molinoff PB, Schalekamp MADH. Hemodynamic and beta-adrenergic receptor adaptations during long-term betaadrenoreceptor blockade. Circulation 1989; 80: 903–14.PubMedCrossRefGoogle Scholar
  18. 18.
    Narayanan N, Derby J. Effects of age on muscarinic cholinergic receptors in rat myocardium. Can J Physiol Pharmacol 1983; 61: 822–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Michel MC, Beckeringh JJ, Ikezono K, Kretsch R, Brodde OE. Lymphocyte beta-2 adrenoreceptors mirror precisely beta-2-adrenoreceptor, but poorly beta-1 adrenoreceptor changes in the human heart. J Hypertens 1986; 4(Suppl 6): S215–S218.Google Scholar
  20. 20.
    Maisel AS, Ziegler MG, Carter S, Insel PA, Motulsky HJ. In vivo regulation of betaadrenergic receptors on mononuclear leukocytes and heart. Assessment of receptor compartmentation after agonist infusion and acute aortic constriction in guinea pigs. J Clin Invest 1988; 82: 2038–44.PubMedCrossRefGoogle Scholar
  21. 21.
    Maisel AS, Phillips C, Michel MC, Ziegler MG, Carter SC. Regulation of cardiac betaadrenergic receptors by captopril. Implications for congestive heart failure. Circulation 1989; 80: 669–75.Google Scholar
  22. 22.
    Delforge J, Janier M, Syrota A et al. Noninvasive quantification of muscarinic receptors in vivo with positron emission tomography in the dog heart. Circulation 1990; 2: 1494–504.CrossRefGoogle Scholar
  23. 23.
    Delforge J, Syrota A, Mazoyer BM. Experimental design optimisation: theory and application to estimation of receptor model parameters using dynamic positron emission tomography. Phys Med Biol 1989; 34: 419–35.PubMedCrossRefGoogle Scholar
  24. 24.
    Delforge J, Syrota A, Mazoyer BM. Identifiability analysis and parameter identification of an in vivo ligand-receptor model from PET data. IEEE Trans Biomed Engin 1990; 37: 653–61.CrossRefGoogle Scholar
  25. 25.
    Heitz A, Schwartz J, Velly J. β-adrenoreceptors of the human myocardium: determination of β1 and β2 subtypes by radioligand binding. Br J Pharmacol 1983; 80: 711–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Robberecht P, Delhaye M, Taton G et al. The human heart β-adrenergic receptors I. Heterogeneity of the binding sites. Presence of 50% β1 and 50% β2-adrenergic receptors. Mol Pharmacol 1983; 24: 169–73.PubMedGoogle Scholar
  27. 27.
    Cohn JN, Levine TB, Olivari MT et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984; 311: 819–23.CrossRefGoogle Scholar
  28. 28.
    Bristow MR, Ginsburg R, Minobe W et al. Decreased catecholamine sensitivity and β-adrenergic receptor density in failing human hearts. N Engl J Med 1982; 307: 205–11.PubMedCrossRefGoogle Scholar
  29. 29.
    Wagner HN. Positron emission tomography in assessment of regional stereospecificity of drugs. Biochem Pharmacol 1988; 37: 51–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Staehelin M, Hertel C. [3H] CGP-12177, a β-adrenergic ligand suitable for measuring cell surface receptors. J Receptor Res 1983; 3: 35–43.Google Scholar
  31. 31.
    Seto M, Syrota A, Crouzel C et al. Beta-adrenergic receptors in the dog heart characterized by 11C-CGP 12177 and PET [abstract]. J Nucl Med 1986; 27: 949.Google Scholar
  32. 32.
    Law MP, Burgin J. Evaluation of CGP-12177 for characterization of β-adrenergic receptors by PET: in vivo studies in rat [abstract]. J Nucl Med 1989; 30: 766–7.Google Scholar
  33. 33.
    Law MP. Characterization of β-adrenoreceptors in vivo using [3H]CGP-12177. In: Szabadi E, Bradshaw CM, editors. Pharmacology of adrenoreceptors. Basel: Birkhauser Verlag, 1990: 7–8.Google Scholar
  34. 34.
    Van Waarde A, Meeder JG, Blanksma PK et al. Suitability of CGP12177 and CGP 26505 for quantitative imaging of β-adrenoceptors. Nucl Med Biol (Submitted).Google Scholar
  35. 35.
    Delforge J, Nakajima K, Syrota A et al. PET investigation of β-adrenergic receptors using CGP 12177 [abstract]. J Nucl Med 1989; 30: 825.Google Scholar
  36. 36.
    Delforge J, Syrota A, Lancon JP et al. Cardiac β-adrenergic receptor density measured in vivo using PET, CGP 12177, and a new graphical method. J Nucl Med 1991; 32: 739–48.PubMedGoogle Scholar
  37. 37.
    Brady F, Luthra SK, Tochon-Danguy H et al. Towards a chiral precursor for the automated radiosynthesis of carbon-11 labelled S-CGP 12177 [abstract]. J Label Compounds Radiopharml 1991;30:251.Google Scholar
  38. 38.
    Antoni G, Ulin J, Långström B. Synthesis of the 11C-labelled β-adrenergic receptor ligands atenolol, metoprolol and propranolol. Int J Appl Radiat Isotop 1989; 40: 561–4.CrossRefGoogle Scholar
  39. 39.
    Berridge MS, Terris AH, Vesselle JM. [C-11]-carazolol: Synthesis and biodistribution of a ligand for imaging beta-adrenergic receptors [abstract]. J Nucl Med 1991; 32: 1097.Google Scholar
  40. 40.
    Kinsey BM, Tewson TJ. Fluorine-18 fluoroalkyl derivatives of carazolol: Potential ligands for the in vivo studies of the β-adrenergic receptor [abstract]. J Label Compounds Radiopharm 1991; 30: 385–6.Google Scholar
  41. 41.
    Prenant C, Sastre J, Crouzel C, Syrota A. Synthesis of 11C-pindolol. J Label Compounds Radiopharm 1987; 24: 227–32.CrossRefGoogle Scholar
  42. 42.
    Tewson TJ, Kinsey BM, Franceschini MP. Synthesis of fluorine-18 fluoroalkyl pindolol derivatives: ligands for the β-adrenergic receptor [abstract]. J Label Compounds Radiopharm 1991; 30: 385–6.Google Scholar
  43. 43.
    Berger G, Prenant C, Sastre J, Syrota A, Comar D. Synthesis of a β blocker for heart visualization: [11C]Practolol. Int J Appl Radiat Isotop 1983; 34: 1556–7.CrossRefGoogle Scholar
  44. 44.
    Berger G, Mazière M, Prenant C, Sastre J, Syrota A, Comar D. Synthesis of 11C-propranolol. J Radioanal Chem 1982; 74: 301.Google Scholar
  45. 45.
    Boullais C, Crouzel C, Syrota A. Synthesis of 4-(3-t-butylamino—2-hydroxypropoxy)—benzimidazol-2-(11C)-one (CPG 12177). J Label Compounds Radiopharm 1986; 23: 565–7.CrossRefGoogle Scholar
  46. 46.
    Sisson JC, Wieland DM, Johnson JW et al. Scintigraphy of adrenergic receptors and neurons in myocardial infarcts [abstract]. J Nucl Med 1989; 30: 767.Google Scholar
  47. 47.
    Wieland DM, Rosenspire KC, Hutchins GD et al. Neuronal mapping of the heart with 6-[18F]fluorometaraminol. J Med Chem 1990; 33: 956–64.PubMedCrossRefGoogle Scholar
  48. 48.
    Wieland DM, Rosenspire KC, Hutchins GD, Schwaiger M. Validation of 6-[18F] fluorometaraminol (FMR) for positron tomography [abstract]. Circulation 1988; 78 (Suppl 2): 598.Google Scholar
  49. 49.
    Mislankar SG, Gildersleeve DL, Wieland DM, Massin CC, Mulholland GK, Toorongian SA. 6-[18F] Fluorometaraminol: a radiotracer for in vivo mapping of adrenergic nerves of the heart. J Med Chem 1988; 31: 362–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Schwaiger M, Guibourg H, Rosenspire KC et al. Effect of regional myocardial ischemia on sympathetic nervous system as assessed by fluorine-18-metaraminol. J Nucl Med 1990; 31: 1352–7.PubMedGoogle Scholar
  51. 51.
    Rosenspire KC, Gildersleeve DL, Massin CC, Mislankar SG, Wieland DM. Metabolic fate of the heart agent [18F]6-fluorometaraminol. Nucl Med Biol 1989; 16: 735–9.Google Scholar
  52. 52.
    Rosenspire KC, Haka MS, Van Dort ME et al. Synthesis and preliminary evaluation of carbon-11-meta-hydroxyephedrine: A false transmitter agent for heart neuronal imaging. J Nucl Med 1990; 31: 1328–34.PubMedGoogle Scholar
  53. 53.
    Wieland DM, Hutchins GD, Rosenspire KC et al. [C-11]hydroxyephedrine (HED): A high specific activity alternative to 6-[F-18]fluorometaraminol (FMR) for heart neuronal imaging. J Nucl Med 1989; 30: 767–9.Google Scholar
  54. 54.
    Wieland DM, Rosenspire KC, Van Dort ME, Haka MS, Jung YW, Gildersleeve DL. Search for a non-metabolizable PET tracer for heart neuronal imaging [abstract]. J Label Compounds Radiopharm 1991; 30: 283.Google Scholar
  55. 55.
    Schwaiger M, Kalff V, Rosenspire KC et al. Noninvasive evaluation of sympathetic nervous system in human heart by positron emission tomography. Circulation 1990; 82: 457–64.PubMedCrossRefGoogle Scholar
  56. 56.
    Schwaiger M, Hutchins G, Rosenspire KC, Haka M, Wieland DM. Quantitative evaluation of the sympathetic nervous system by PET in patients with cardiomyopathy [abstract]. J Nucl Med 1990; 31: 792.Google Scholar
  57. 57.
    Goldstein DS, Chang PC, Eisenhofer G et al. Positron emission tomographic imaging of cardiac sympathetic innervation and function. Circulation 1990; 81: 1606–21.PubMedCrossRefGoogle Scholar
  58. 58.
    Ding YS, Fowler JS, Gatley SJ, Dewey SL, Wolf AP, Schlyer DJ. Synthesis of high specific activity 6-[18F]fluorodopamine for positron emission tomography studies of sympathetic nervous tissue. J Med Chem 34: 861–Google Scholar
  59. 59.
    Ehrin E, Luthra SK, Crouzel C, Pike VW. Preparation of carbon-11 labelled prazosin, a potent and selective alpha1adrenoreceptor antagonist. J Label Compounds Radiopharm 1988; 25: 177–83.CrossRefGoogle Scholar
  60. 60.
    Mazière M, Comar D, Godot JM, Collard P, Cepeda C, Naquet R. In vivo characterization of myocardium muscarinic receptors by positron emission tomography. Life Sci 1981; 29: 2391–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Syrota A, Dormont D, Berger A et al. C-11 ligand binding to adrenergic and muscarinic receptors of the human heart studied in vivo by PET [abstract]. J Nucl Med 1983; 24: P20.Google Scholar
  62. 62.
    Syrota A, Paillotin G, Davy JM, Aumont MC. Kinetics of in vivo binding of antagonist to muscarinic cholinergic receptor in the human heart studied by positron emission tomography. Life Sci 1984; 35: 937–45.PubMedCrossRefGoogle Scholar
  63. 63.
    Syrota A, Comar D, Paillotin G et al. Muscarinic cholinergic receptor in the human heart evidenced under physiological conditions by positron emission tomography. Proc Natl Acad Sci USA 1985; 82: 584–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Syrota A, Le Guludec D, Prenant C et al. PET investigation of myocardial muscarinic cholinergic acetylcholine receptor in patients with hyper-and hypothyroidism [abstract]. J Nucl Med 1988; 29: 808.Google Scholar
  65. 65.
    Charbonneau P, Syrota A, Crouzel C, Valois JM, Prenant C, Crouzel M. Peripheral-type benzodiazepine receptors in the living heart characterized by positron emission tomography. Circulation 1986; 73: 476–83.PubMedCrossRefGoogle Scholar
  66. 66.
    Camsonne R, Crouzel C, Comar D et al. Synthesis of N-(11C)-methyl,N-(methyl-l-propyl), (chloro-2-phenyl)-l-isoquinoline carboxamide-3 (PK 11195). A new ligand for peripheral benzodiazepine receptors. J Label Compounds Radiopharm 1984; 21: 985–91.CrossRefGoogle Scholar
  67. 67.
    Hashimoto K, Inoue O, Suzuki K, Yamasaki T, Kojima M. Synthesis and evaluation of 11C-PK 11195 for in vivo study of peripheral-type benzodiazepine receptors using positron emission tomography. Ann Nucl Med 1989; 3: 63–71.PubMedCrossRefGoogle Scholar
  68. 68.
    Pascali C, Luthra SK, Pike VW et al. The radiosynthesis of [18F]PK 14105 as an alternative radioligand for peripheral-type benzodiazepine binding sites. Int J Rad Appl Instrum [A] 1990; 41: 477–82.CrossRefGoogle Scholar
  69. 69.
    Watkins GL, Jewett DM, Mudholland GK, Kilbourn MR, Toorongian SA. A captive solvent method for rapid N-[11C]methylation of secondary amides: application to the benzodiazepine, 4′-chlorodiazepam (Ro 5-4864). Int J Rad Appl Instrum [A] 1988; 39: 441–4.CrossRefGoogle Scholar
  70. 70.
    Le Breton C, Crouzel C. Synthesis of [11C]ranitidine: a potential PET imaging agent for H2 receptors in heart. J Label Compounds Radiopharm 1991; 30: 256–7.Google Scholar
  71. 71.
    Yorke JC, Prenant C, Crouzel C. Synthesis of carbon-11 labelled cyclopentyltheophylline: a radioligand for PET studies of adenosine receptors. J Label Compounds Radiopharm 1991; 30: 262–3.Google Scholar
  72. 72.
    Channing MA, Dunn BB, Boring DL, Jacobson KA. Development of a F-18 labeled antagonist for the AI adenosine receptor [abstract]. J Label Compounds Radiopharm 1991; 30: 244.Google Scholar
  73. 73.
    Hwang DR, Mathias CJ, Welch MJ, Lloyd J, Petrillo EW, Eckelman WC. Synthesis and biodistribution of [F-18]-labeled angiotensin converting enzyme inhibitor [F-18]fluorocaptopril [abstract]. J Nucl Med 1990; 31: 738.Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1992

Authors and Affiliations

  • Aren van Waarde
  • Paul K. Blanksma
  • Joan G. Meeder
  • Gerben M. Visser
  • Wiek H. van Gilst

There are no affiliations available

Personalised recommendations