Use of PET Radiopharmaceuticals to Probe Cardiac Receptors

  • Heric Valette
  • Andre Syrota
  • Pascal Merlet
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 165)


Receptors form a class of intrinsic membrane glycoproteins characterized by the high affinity and specificity with which they bind ligands. Receptors are associated directly or indirectly with membrane ion channels, which open or close after a conformational change of the receptor induced by the binding of the neurotransmitter or of an agonist to the specific site. In heart disease, alterations in receptor density, distribution, and subtypes have been widely demonstrated from samples collected by endomyocardial biopsy, during surgery, or at autopsy. Positron emission tomography (PET) now offers the unique possibility of determining in vivo the receptor density in humans. These measurements are based on the synthesis of a radioligand, usually a selective receptor antagonist labeled with a positron-emitting radioisotope such as 11C or 18F. Mathematical compartmental models applied to time-concentration curves obtained during saturation or displacement experiments can provide the values of the myocardial receptor density and of the rate constants of the ligand-receptor interaction. Several receptor classes have been characterized in human heart: beta- and alpha-adrenergic, muscarinic cholinergic, and peripheral-type benzodiazepine. PET can give information on changes in receptor number that are associated with different physiological and pathological processes. Noticeable progress in this field has emerged recently.


Positron Emission Tomography Muscarinic Receptor Receptor Density Positron Emission Tomography Data Muscarinic Receptor Subtype 
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  1. 1.
    Mazière M, Comar D, Godot JM, Collard P, Cepeda P, Naquet R. In vivo characterization of myocardium muscarinic receptors by positron emission tomography. Life Sci 29:2391–2397, 1981.PubMedCrossRefGoogle Scholar
  2. 2.
    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 35:937–945, 1984.PubMedCrossRefGoogle Scholar
  3. 3.
    Syrota A. Positron emission tomography: Evaluation of cardiac receptors. In: Marcus ML, Skorton DJ, Schelbert HR, Wolf GL (eds): Cardiac Imaging—Principles and Practice: A Companion of Braunwald’s Heart Disease. Philadelphia: W.B. Saunders, 1991, pp 1256–1270.Google Scholar
  4. 4.
    Delforge J, Syrota A, Mazoyer B. Experimental design optimization: Theory and application to estimation of receptor model parameters using dynamic positron emission tomography. Phys Med Biol 34:419–435, 1989.PubMedCrossRefGoogle Scholar
  5. 4a.
    Mintun MA, Raichle ME, Kilbourn MR, Wooten GF, Welch MJ. A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol 15:217–227, 1984.PubMedCrossRefGoogle Scholar
  6. 5.
    Farde L, Hall H, Ehrin E, Sedvall G. Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. Science 231:258–261, 1986.PubMedCrossRefGoogle Scholar
  7. 6.
    Perlmutter JS, Larson KB, Raichle ME, Markham J, Mintun MA, Kilbourn MR, Welch MJ. Strategies for in vivo measurement of receptor binding using positron emission tomography. J Cereb Blood Flow Metab 6:154–169, 1986.PubMedCrossRefGoogle Scholar
  8. 7.
    Wong DF, Gjedde A, Wagner HN Jr, Dannais RF, Douglas KH, Links JM, Kuhar MJ. Quantification of neuroreceptors in the living human brain: II. Inhibition studies of receptor density and affinity. J Cereb Blood Flow Metab 6:147–153, 1986.PubMedCrossRefGoogle Scholar
  9. 8.
    Bradbury MWB, Kleeman CR. Stability of the potassium content of cerebrospinal fluid and brain. Am J Physiol 213:519–528, 1967.PubMedGoogle Scholar
  10. 9.
    Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood to brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 3:3–12, 1983.CrossRefGoogle Scholar
  11. 10.
    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 344:419–435, 1989.CrossRefGoogle Scholar
  12. 11.
    Charbonneau P, Syrota A, Boullais C, Crouzel C. Serotonin receptors and lung phagocyte recruitment induced by cigarette smoking detected in vivo by positron emission tomography (abstr). J Nucl Med 27:950, 1986.Google Scholar
  13. 12.
    Molinoff PB. Alpha- and beta-adrenergic receptor subtypes properties, distribution and regulation. Drugs 28(Suppl 2):1–15, 1984.PubMedCrossRefGoogle Scholar
  14. 13.
    Motulsky HJ, Insel PA. Adrenergic receptors in man. Direct identification, physiologic regulation, and clinical alterations. N Engl J Med 307:18–28, 1982.PubMedCrossRefGoogle Scholar
  15. 14.
    Skomedal T, Aass H, Osnes JB. Specific binding of 3H-prazosin to myocardial cells isolated from adult rats. Biochem Pharmacol 33:1897–1906, 1984.PubMedCrossRefGoogle Scholar
  16. 15.
    Story DD, Briley MS, Langer SZ. The effects of chemical sympathectomy with 6-hydroxydopamine on alpha-adrenoceptor and muscarinic cholinoceptor binding in rat heart ventricle. Eur J Pharmacol 57:423–426, 1979.PubMedCrossRefGoogle Scholar
  17. 16.
    Saito K, Kurihara M, Cruciani R, Potter WZ, Saavedra JM. Characterization of beta-1 and beta-2 adrenoceptor subtypes in the rat atrioventricular node by quantitative autoradiography. Circ Res 62:173–177, 1988.PubMedGoogle Scholar
  18. 17.
    Buxton ILO, Brunton LL. Direct analysis of beta-adrenergic receptor subtypes on intact adult ventricular myocytes of the rat. Circ Res 56:126–132, 1985.PubMedGoogle Scholar
  19. 18.
    Freissmuth M, Hausleithner V, Nees S, Buck M, Schütz W. Cardiac ventricular beta-2 adrenoceptors in guinea pigs and rats are localized on the coronary endothelium. Naunyn-Schmiedebergs Arch Pharmacol 334:56–62, 1986.PubMedCrossRefGoogle Scholar
  20. 19.
    Vatner DE, Knight DR, Homey CJ, Vatner SF, Young MA. Subtypes of beta-adrenergic receptors in bovine coronary arteries. Circ Res 59:463–473, 1986.PubMedGoogle Scholar
  21. 20.
    Lathers CM, Levin RM, Spivey WH. Regional distribution of myocardial beta-adrenoceptors in the cat. Eur J Pharmacol 130:111–117, 1986.PubMedCrossRefGoogle Scholar
  22. 21.
    Wei J-W, Sulakhe PV. Regional and subcellular distribution of beta- and alpha-adrenergic receptors in the myocardium of different species. Gen Pharmacol 10:263–267, 1979.PubMedCrossRefGoogle Scholar
  23. 22.
    Murphree SS, Saffitz JE. Delineation of beta-adrenergic receptor subtypes in canine myocardium. Circ Res 63:117–125, 1988.PubMedGoogle Scholar
  24. 23.
    Mukherjee A, Haghani Z, Brady J, Bush L, McBride W, Buja LM, Willerson JT. Differences in myocardial alpha- and beta-adrenergic receptor numbers in different species. Am J Physiol (Heart Circ Physiol 14) 245:H957–H961, 1983.Google Scholar
  25. 24.
    Summer RJ. Molenaar P, Russel F, Elnatan J, Jones CR, Buxton BF, Chang V, Hambley J. Co-existence and localization of ßl and ß2-adrenoreceptors in the human heart. Eur Heart J 10(Suppl B):11-18, 1989.Google Scholar
  26. 25.
    Stiles GL, Taylor S, Lefkowitz RJ. Human cardiac beta-adrenergic receptors: Subtype heterogeneity delineated by direct ligand binding. Life Sci 33:467–473, 1983.PubMedCrossRefGoogle Scholar
  27. 26.
    Golf S, Lfvstad R, Hansson V. Beta-adrenoceptor density and relative number of beta-adrenoceptor subtypes in biopsies from human right atrial, left ventricular and right ventricular myocard. Cardiovasc Res 19:636–641, 1985.PubMedCrossRefGoogle Scholar
  28. 27.
    Nanoff C, Freissmuth M, Schütz W. The role of a low beta-1 adrenoceptor selectivity of [3H]CGP-12177 for resolving subtype-selectivity of competitive ligands. Naunyn-Schmiedebergs Arch Pharmacol 336:519–525, 1987.PubMedGoogle Scholar
  29. 28.
    Staehelin M, Simons P, Jaeggik, Wigger N. CGP-12177. A hydrophilic beta-adrenergic receptor radioligand reveals high affinity binding of agonists to intact cells. J Biol Chem 258:3496–3502, 1983.PubMedGoogle Scholar
  30. 29.
    Hertel C, Muller P, Portenier H, Staehelin M. Determination of the desensitization of beta-adrenergic receptors by [3H]CGP-12177. Biochem J 216:669–674, 1983.PubMedGoogle Scholar
  31. 30.
    Crozatier B, Bo Su J, el Houda Bouanani N. Species differences in myocaardial ß-adrenergic receptor regulation in response to hyperthyroidism. Circ Res 69:1234–1243, 1991.PubMedGoogle Scholar
  32. 31.
    Hirschowitz BI et al. (eds). Subtypes of muscarinic receptors. Trends Pharma Sci (Suppl): 1984.Google Scholar
  33. 32.
    Hammer R, Berrie CP, Birdsall NJM, Burgen AS, Hulme EC. Pirenzepine distinguishes between different subclasses of muscarinic receptors. Nature 283:90–92, 1980.PubMedCrossRefGoogle Scholar
  34. 33.
    Giachetti A, Micheletti R, Montagna E. Cardioselective profile of AF-DX 116, a muscarinic M2 receptor antagonist. Life Sci 38:1663–1672, 1986.PubMedCrossRefGoogle Scholar
  35. 34.
    Hammer R, Giraldo E, Schiavi GB, Monferini E, Ladinsky H. Binding profile of a novel cardioselective muscarininc antagonist, AF-DX 116, to membranes of peripheral tissues and brain in the rat. Life Sci 38:1653–1662, 1986.PubMedCrossRefGoogle Scholar
  36. 35.
    Doods HN, Mathy M-J, Davidesko D, Van Charldorp KJ, Dejonge A, Van Zwietten PA. Selectivity of muscarinic antagonists in radioligand and in vivo experiments for the putative Ml, M2 and M3 receptors. J Pharmacol Exp Ther 242:257–262, 1987.PubMedGoogle Scholar
  37. 36.
    Watson M, Yamamura HI, Roeske WR. [3H]Pirenzepine and (−)-[3H]quinuclidinyl benzilate binding to rat cerebral cortical and cardiac muscarinic cholinergic sites. I. Characterization and regulation of agonist binding to putative muscarinic subtypes. J Pharmacol Exp Ther 237:411–418, 1986.PubMedGoogle Scholar
  38. 37.
    Gossuin A, Maloteaux JM, Trouet, Laduron P. Differentiation between ligand trapping into intact cells and binding on muscarinic receptors. Biochim Biophys Acta 804:100–106, 1984.PubMedCrossRefGoogle Scholar
  39. 38.
    Brown JH, Goldstein D. Analysis of cardiac muscarinic receptors recognized selectively by nonquaternary but not by quaternary ligands. J Pharmacol Exp Ther 238:580–586, 1986.PubMedGoogle Scholar
  40. 39.
    Syrota A, Comar D, Paillotin G, Davy JM, Aumont MC, Stulzaft O, Mazière B. Muscarinic cholinergic receptor in the human heart evidenced under physiological conditions by positron emission tomography. Proc Natl Acad Sci USA 82:584–588, 1985.PubMedCrossRefGoogle Scholar
  41. 40.
    Yamada S, Yamazawa T, Harada Y, Yamamura HI, Nakayama KN. Muscarinic receptor subtype in porcine coronary artery. Eur J Pharmacol 150:373–376, 1988.PubMedCrossRefGoogle Scholar
  42. 41.
    Pelc LR, Gross GJ, Warltier DC. Changes in regional myocardial perfusion by muscarinic receptor subtypes in dogs. Cardiovasc Res 20:482–489, 1986.PubMedCrossRefGoogle Scholar
  43. 42.
    Pelc LR, Daemmgen JW, Gross GJ, Warltier DC. Muscarinic receptor subtypes mediating myocardial blood flow redistribution. J Cardiovasc Pharmacol 11:424–431, 1988.PubMedCrossRefGoogle Scholar
  44. 43.
    Hynes MR, Banner W Jr, Yamamura HI, Duckless SP. Characterization of muscarinic receptors of the rabbit ear artery smooth muscle and endothelium. J Pharmacol Exp Ther 238:100–105, 1986.PubMedGoogle Scholar
  45. 44.
    Duckies SP. Vascular muscarinic receptors: Pharmacological characterization in the bovine coronary artery. J Pharmacol Exp Ther 246:929–934, 1988.Google Scholar
  46. 45.
    Stephenson JA, Summers RJ. Autoradiographic analysis of receptors on vascular endothelium. Eur J Pharmacol 134:35–43, 1987.PubMedCrossRefGoogle Scholar
  47. 46.
    Parola AL, Yamamura HI, Laird II HE. Peripheral-type benzodiazepine receptors. Life Sci 52:1329–1342, 1993.PubMedCrossRefGoogle Scholar
  48. 47.
    Benavides J, Guilloux F, Rufat P, Uzan A, Renault C, Dubroeucq MC, Gueremy C, Le Fur G. In vivo labelling in several rat tissues of peripheral type benzodiazepine binding sites. Eur J Pharmacol 99:1–7, 1984.PubMedCrossRefGoogle Scholar
  49. 48.
    Syrota A, Girault M, Pocidalo JJ, Yudilevich DL. Endothelial uptake of amino acids, sugars, lipids and prostaglandins in rat lung. Am J Physiol 243 (Cell Physiol 12):C20–C26.Google Scholar
  50. 49.
    Hugues B, Bergmann SR, Corr PB, Sobel BE. External detection of β-adrenoreeeptors with 125I-hydroxybenzylpindolol in isolated perfused hearts. Nucl Med Biol 135:565–571, 1986.Google Scholar
  51. 50.
    Chaumet-Riffaud Ph, Girault M, Syrota A. Characterization of muscarinic cholinergic receptors in the isolated perfused rat heart. J Physiol (Lond) 348:11P, 1984.Google Scholar
  52. 51.
    Ehrin E, Luthra SK, Crouzel C, Pike VW. Preparation of carbon-11 labelled prazosin, a potent and selective alpha-1 adrenoceptor antagonist. J Label Compds Radiopharm 25: 177–183, 1988.CrossRefGoogle Scholar
  53. 52.
    Delforge J, Janier M, Syrota A, Crouzel C, Vallois JM, Cayla J Lançon JP, Mazoyer B. Noninvasive quantification of muscarinic receptors in vivo with positron emission tomography in the dog heart. Circulation 82:1494–1504, 1990.PubMedCrossRefGoogle Scholar
  54. 53.
    Galper JB, Smith TW. Properties of muscarinic acetylcholine receptors in heart cell cultures. Proc Natl Acad Sci USA 75:5831–5835, 1978.PubMedCrossRefGoogle Scholar
  55. 54.
    Berger G, Mazière M, Prenant C, Sastre J, Syrota A, Comar D. Synthesis of 11C-propranolol. J Radioanal Chem 74:301–306, 1982.CrossRefGoogle Scholar
  56. 55.
    Berger G, Prenant C, Sastre J, Syrota A, Comar D. Synthesis of a beta-blocker for heart visualization: [11C]practolol. IntJ Appl Radiât Isot 34:1556–1557, 1983.CrossRefGoogle Scholar
  57. 56.
    Prenant C, Sastre J, Crouzel C, Syrota A. Synthesis of 11C-pindolol. J Label Compds Radiopharm 24:227–232, 1987.CrossRefGoogle Scholar
  58. 57.
    Antoni G, UlinJ, Längström B. Synthesis of the 11C-labelled β-adrenergic ligands atenolol, metoprolol and propranolol. Appl Radiat Isot 40:561–572, 1989.CrossRefGoogle Scholar
  59. 58.
    Hammadi A, Crouzel C. Asymetrie synthesis of (2S) and (2R)-4-(butylamino-2-hydroxypropoxy-benzamidazol-2-C-11) one ((S) and (R) (C-11 CGP 12177 from optically active precursors. J Lab Compds Radiopharm 29:681–690, 1991.CrossRefGoogle Scholar
  60. 59.
    Berridge MS, Terris HA, VesselleJM. Preparation and in vivo binding or 11C-Carazolol, a radiotracer for the beta-adrenergic receptor. Nucl Med Biol 19:563–567, 1992.Google Scholar
  61. 59.
    Heitz A, Schwartz J, Velly J. Beta-adrenoceptors of the human myocardium: determination of βl and β2 subtypes by radioligand binding. Br J Pharmacol 80:711–717, 1983.PubMedGoogle Scholar
  62. 60.
    de Groote TJ, van Warde A, Eisinga PH, Visser GM, Brodde OE, Vaalburg W. Synthesis and evaluation of l’-(18-F)fluorometoprolol as a potential tracer for the visualization of β-adrenoceptors with PET. Nucl Med Biol 20:637–642, 1993.CrossRefGoogle Scholar
  63. 61.
    Dormont D, Syrota A, Berger G, Maziere M, Prenant C, SastreJ, Davy JM, Aumont MC, Motté G, Gourgon R. 11C ligand binding to adrenergic and muscarinic receptors in the human heart studied in vivo by PET. J Nucl Med 24:P20, 1983.Google Scholar
  64. 62.
    Delforge J, Syrota A, Lancon JP, Nakajima K, Loc’h D, Janier M, Vallois JM, Cayla J, Crouzel C. Cardiac beta-adrenergic receptor density measured in vivo using PET, CGP 12177 and a new graphical method. J Nucl Med 32:739–748, 1991.PubMedGoogle Scholar
  65. 63.
    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 73:476–483, 1986.PubMedCrossRefGoogle Scholar
  66. 64.
    Delforge J, Le Guludec D, Syrota A, Bendriem B, Crouzel C, Slama M, Merlet P. Quantification of myocardial muscarinic receptors with PET in Humans. J Nucl Med 34:981–991, 1993.PubMedGoogle Scholar
  67. 65.
    Lew WYW, Hryshko LV, Bers DM. Dihydropyridine receptors are primarily functional L-type calcium channels in rabbit ventricular myocytes. Circ Res 69:1139–1145, 1991.PubMedGoogle Scholar
  68. 66.
    Merlet P, Delforge J, Syrota A, et al. Positron emission tomography with 11C-CGP 12177 to assess β-adrenergic receptor concentration in idiopathic dilated cardiomyopathy. Circulation 87:1169–1178, 1993.PubMedGoogle Scholar
  69. 67.
    Vera-Ruiz H, Marcus CS, Pike VW, Coenen HH, Fowler JS, Meyer GJ, Cox PH, Vaalburg W, Cantneau R, Helus F, Lambrecht RM. Report of an International Atomic Energy Agency’s Advisory group on “Quality control of cyclotron-produced radiopharmaceuticals.” Nucl Med Biol 17:445–456, 1990.Google Scholar
  70. 68.
    Stöcklin G, Pike VW (eds): Radiopharmaceuticals for Positron Emission Tomography. Methodological Aspects. Norwell, MA: Kluwer Academic, 1993, pp 91–147.Google Scholar
  71. 69.
    Hoffman EJ, Phelps ME. PET: Principle and quantitation. In: Phelps M, Mazziotta J, Schelbert H (eds): PET and Autoradiography: Principles and Applications for Brain and Heart. New York: Raven Press, 1986, pp 237–286.Google Scholar
  72. 70.
    Phelps ME, Huang SC, Hoffman EJ, et al. Tomographic measurement of local cerebral glucose metabolic rate in man with (18F) fluorodeoxyglucose: validation of method. Ann Neurol 6:371–388, 1979.PubMedCrossRefGoogle Scholar
  73. 71.
    Weinberg IN, Huang SC, Hoffman EJ, et al. Validation of PET-acquired input functions for cardiac studies. J Nucl Med 29:241–247, 1988.PubMedGoogle Scholar
  74. 72.
    Herrero P, Markhan J, Bergmann SR. Quantification of MBF with H2 15O and positron emission tomography: Assessment and error analysis of mathematical approach. J Comput Assist Tomogr 13:862–873, 1989.PubMedCrossRefGoogle Scholar
  75. 73.
    Huang SC, Barrio JR, Yu DC, et al. Modelling approach for separating blood time-activity curves in PET studies. Phys Med Biol 36:749–761, 1991.PubMedCrossRefGoogle Scholar
  76. 74.
    Hutchins GD, Caraher JM, Raylman RR. A region of interest strategy for minimizing resolution distortion in quantitative myocardial PET studies. J Nucl Med 33:1243–1250, 1992.PubMedGoogle Scholar
  77. 75.
    Bendriem B, Delforge J, Frouin V, Syrota A. Effect of instrumental errors on the in vivo measurement of receptor concentration in the heart using PET (abstr). J Nucl Med 33:882, 1992.Google Scholar

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© Kluwer Academic Publishers 1996

Authors and Affiliations

  • Heric Valette
  • Andre Syrota
  • Pascal Merlet

There are no affiliations available

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