Subscribe to RSS
DOI: 10.1055/s-0038-1623898
Radioligands for imaging myocardial α- and β-adrenoceptors[*]
Radioliganden für die Bildgebung kardialer α- und β-AdrenozeptorenPublication History
Received:
02 December 2002
05 December 2002
Publication Date:
10 January 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00034924/200301/lookinside/thumbnails/10-1055-s-0038-1623898_de-1.jpg)
Summary
Alpha- and beta-adrenoceptors play an important role in the control of heart function. According to their molecular, biological, and pharmacological characteristics, they are subdivided into α1-, α2- and β1-, β2-, β3-, β4-adrenoceptors. In cardiac disease, there is often a selective downregulation of β1-adrenoceptors associated with a relative increase in β2- and α1-adrenoceptors. Functional imaging techniques like single-photon emission tomography (SPECT) and positron emission tomography (PET) provide the unique capability for non-invasive assessment of cardiac adrenoceptors. Radioligands with high specific binding to cardiac α- and β-adrenoceptors suitable for radiolabelling are required for clinical studies. The non-selective β-adrenoceptor antagonist [11C]CGP-12177 was used to quantify β-adrenoceptor density using PET in patients with heart disease. New non-selective ligands (e. g. [11C]CGP-12388, [18F]CGP-12388, [11C]carazolol and [18F]fluorocarazolol) are currently evaluated; β1-selective radioligands (e. g. [11C]CGP-26505, [11C]bisoprolol, [11C]HX-CH 44) and β2-selective radioligands (e. g. [11C]formoterol, [11C]ICI-118551) were assessed in animals. None of them turned out as suitable for cardiac PET.
Potential radioligands for imaging cardiac α1-adrenoceptors are based on prazosin. Whereas [11C]prazosin shows low specific binding to myocardium, its derivative [11C]GB67 looks more promising. The putative α2-adrenoceptor radioligand [11C]MK-912 shows high uptake in rodent myocardium but has not yet been evaluated in man.
A number of radioligands were evaluated for assessing cardiac adrenoceptors using PET. New radioligands are needed to provide more insight into cardiac pathophysiology which may influence the therapeutic management of patients with cardiovascular disease.
Zusammenfassung
Alpha- und beta-Adrenozeptoren spielen eine wichtige Rolle für die Herzfunktion. Nach ihren molekularen, biologischen und pharmakologischen Eigenschaften werden sie in α1-, α2- und β1-, β2-, β3-, β4-Adrenozeptoren eingeteilt. Kardiale Erkrankungen sind häufig durch eine selektive Down-Regulation der β1-Adrenozeptoren gekennzeichnet, die mit relativer Zunahme der β2- und α1-Adrenozeptoren einhergeht. Die funktionellen bildgebenden Verfahren Einzel-Photonen-Emissionstomographie (SPECT) und Positronenemissionstomographie (PET) ermöglichen es, kardiale Adrenozeptoren nicht invasiv zu untersuchen. Für klinische Studien müssen dazu geeignete Radioliganden entwickelt werden, die mit hoher Spezifität an kardiale α- bzw. β-Adrenozeptoren binden und die radioaktiv markiert werden können.
Der nicht selektive β-Adrenozeptorantagonist [11C]CGP-12177 wurde erfolgreich zur Quantifizierung der β-Adrenozeptordichte mittels PET bei herzkranken Patienten eingesetzt. Neue nicht selektive Radioliganden (z.B. [11C]CGP-12388, [18F]CGP-12388, [11C]Carazolol, [18F]Fluorcarazolol) werden zurzeit evaluiert. Einige β1-selektive (z.B. [11C]CGP-26505, [11C]Bisoprolol, [11C]HX-CH 44) und β2-selektive Radioliganden ([11C]Formoterol, [11C]ICI-118551) wurden im Tierversuch erprobt, doch als Tracer für das Herz-PET waren sie ungeeignet.
Zur Darstellung der kardialen α1-Adrenozeptoren wurden geeignete Radioliganden basierend auf Prazosin entwickelt. Während [11C]Prazosin nur eine geringe spezifische Bindung im Herzen zeigte, scheint dessen Derivat [11C]GB67 verheißungsvoll zu sein. Der 11C-markierte α2-Adrenozeptorantagonist [11C]MK-912 zeigte eine hohe myokardiale Aufnahme bei Nagern, wurde aber am Menschen noch nicht untersucht.
Bisher wurde eine Reihe von Radioliganden zur Darstellung der kardialen Adrenozeptoren mittels PET untersucht. Weitere Liganden sollten entwickelt werden mit dem Ziel, Einblicke in die Pathophysiologie kardialer Erkrankungen zu erlangen, die das therapeutische Vorgehen bei Patienten mit kardiovaskulären Erkrankungen beeinflussen könnten.
* Diese Arbeit ist Prof. Dr. Dr. h. c. Heinz Hundeshagen zum 75. Geburtstag gewidmet.
-
References
- 1 Ahlquist RP. A study of adrenotropic receptors. Am J Physiol 1948; 153: 586-600.
- 2 Berridge MJ. Inositol triphosphate and diacylglycerol: two interacting second messengers. Annu Rev Biochem 1987; 56: 159-93.
- 3 Bristow MR, Ginsburg R. 2 receptors present on myocardial cells in human ventricular myocardium. Am J Cardiol 1986; 57: 3F-6F.
- 4 Bristow MR, Hershberger RE, Port DJ. et al. 1 and 2 adrenertgic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. Mol Pharmacol 1989; 35: 295-303.
- 5 Bristow MR, Minobe W, Rasmussen R. et al. Alpha-1 adrenergic receptors in the nonfailing and failing human heart. J Pharmacol Exp Ther 1988; 247: 1039-45.
- 6 Bristow MR. Changes in myocardial and vascular receptors in heart failure. JACC 1993; 22: 61A-71A.
- 7 Brodde OE, Karad K, Zerkowski HR. et al. Coexistence of 1- and 2-adrenoceptors in human right atrium. Circ Res 1983; 53: 752-8.
- 8 Brodde OE, Michel MC. Adrenergic and muscarinic receptors in the human heart. Pharmacol Rev 1999; 51: 651-90.
- 9 Brodde OE, Schuler S, Kretsch R. et al. Regional distribution of -adrenoceptors in the human heart: coexistence of function 1- and 2-adrenoceptors in both atria and ventricles in severe congestive cardiomyopathy. J Cardiovasc Pharmacol 1986; 8: 1235-42.
- 10 Brodde OE. 1- and 2-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure. Pharmacol Rev 1991; 43: 203-42.
- 11 Bylund DB, Ray-Prenger C, Murphy TJ. Alpha-2A and alpha-2B adrenergic receptor subtypes: antagonist binding in tissues and cell lines containing only one subtype. J Pharamcol Exp Ther 1988; 245: 600-7.
- 12 Carlsson E, Dahlhof CG, Hedberg A. et al. Differentiation of cardiac chronotropic and isotropic effects of -adrenoceptor agonists. Naunyn Schmiedbergs Arch Pharmacol 1977; 300: 101-5.
- 13 Davenport RJ, Law MP, Pike VW. et al. Radio-synthesis of [11C]GB67 – a potential radioligand for the study of 1-adrenoceptors with PET. J Labelled Compd Radiopharm 1995; 37: 387-8.
- 14 Davenport RJ, McCarron JA, Dowsett K. et al. A simply automated process for 11C-carboxylation reactions leading to 11C-labelled radio-pharmaceuticals in high specific radioactivity. J Labelled Compd Radiopharm 1997; 40: 309-11.
- 15 Delforge J, Syrota A, Lanon JP. et al. Cardiac beta-adrenergic receptor density measured in vivo using PET, CGP 12177 and a new graphical method. J Nucl Med 1991; 32: 739-48.
- 16 Delhaye M, Taton G, de Neef P. et al. The human heart -adrenergic receptors. Mol Pharmacol 1983; 24: 169-73.
- 17 Doze P, Elsinger PM, van Waarde A. et al. Quantification of -adrenoceptor density in the human heart with (S)-[11C] CGP 12388 and a tracer kinetic model. Eur J Nucl Med 2002; 29: 295-304.
- 18 Elsinga PH, Doze P, van Waarde A. et al. Imaging of beta-adrenoceptors in the human thorax using (S)-[(11)C]CGP12388 and positron emission tomography. Eur J Pharmacol 2001; 433: 173-6.
- 19 Elsinga PH, van Waarde A, Jaeggi KA. et al. Synthesis and evaluation of (S)-4-(3-(2’-[11C] isopropylamino)-2-hydroxypropoxy)-2H-benzimidazol-2-one ((S)-[11C]CGP 12388) and (S)-4-(3-((1’-[18F]-fluoroisopropyl)amino)-2-hydroxypropoxy)-2H-benzimidazol-2-one ((S)-[18F]fluoro-CGP 12388) for visualization of beta-adrenoceptors with positron emission tomography. J Med Chem 1997; 40: 3829-35.
- 20 Giardina D, Brasili L, Gregori M. et al. Structure activity relationships in prazosin-related compounds. Effects of replacing a piperazine ring with an alkanediamine moiety on -blocking activity. J Med Chem 1989; 32: 50-5.
- 21 Hedberg A, Kempf F, Josephson ME. et al. Coexistence of 1 and 2 adrenergic receptors in the human heart: effects of treatment with receptor antagonists or calcium entry blockers. J Pharmacol Exp Ther 1985; 234: 561-8.
- 22 Heitz A, Schwartz J, Velly J. -adrenoceptors of the human myocardium: determination of 1 and 2 subtypes by radioligand binding. Br J Pharmacol 1983; 80: 711-7.
- 23 Heusch G. -adrenergic mechanisms in myocardial ischemia. Circulation 1990; 81: 1-13.
- 24 Inoue H, Zipes DP. Results of sympathetic denervation in the canine heart: supersensitivity that may be arrhythmogenic. Circulation 1987; 75: 877-87.
- 25 Kaumann AJ, Lemoine H. B2-adrenoceptor-mediated positive inotropic effect of adrenaline in human ventricular myocardium: quantitative discrepancies with binding and adenylate cyclase stimulation. Naunyn Schmiedeberg Arch Pharmacol 1987; 335: 403-11.
- 26 Law MP, Osman S, Pike VW. et al. Evaluation of [11C]GB67, a novel radioligand for imaging 1-adrenoceptors with positron emission tomography. Eur J Nucl Med 2000; 27: 7-17.
- 27 Lerman BB. Response on nonreentrant catecholamine-mediated ventricular tachycardia to endogenous adenosine and acetylcholine. Evidence for myocardial receptor-mediated effects. Circulation 1993; 87: 382-90.
- 28 Moresco RM, Matarrese M, Soloviev D. et al. Synthesis and in vivo evaluation of [11C]ICI 118551 as a putative subtype selective beta2-adrenergic radioligand. Int J Pharm 2000; 204: 101-9.
- 29 Nanoff C, Freissmuth M, Schütz W. The role of a low β1-adrenoceptor selectivity of [3H]CGP-12177 for resolving subtype-selectivity of competitive ligands. Naunyn Schmiedeberg’s Arch Pharmacol 1987; 336: 519-25.
- 30 Osman S, Law MP, Daveport RJ. et al. Fate and metabolism of the prospective myocardial 1-adrenoceptor radioligand [N-methylamido-11C]GB67 in rats. J Labelled Compd Radiopharm 1997; 40: 170-2.
- 31 Osman S, Law MP, Pike VW. et al. Evaluation of the prospective α1-adrenoceptor radioligand, [11C]GB67, in human volunteers – myocardial uptake and assessment of radioactive metabolites in plasma. J Labelled Compd Radiopharm 1999; 42: S22-S24.
- 32 Pike VW, Law MP, Osman S. et al. Selection, design and evaluation of new radioligands for PET studies of cardiac adrenoceptors. Pharm Acta Helv 2000; 74: 191-200.
- 33 Schäfers M, Dutka D, Rhodes CG. et al. Myocardial pre- and postsynaptic autonomic dysfunction in hypertrophic cardiomyopathy. Circ Res 1998; 82: 57-62.
- 34 Schäfers M, Lerch H, Wichter T. et al. Cardiac sympathetic innervation in patients with idiopathic right ventricular outflow tract tachycardia. J Am Coll Cardiol 1998; 32: 181-6.
- 35 Schäfers M, Riemann B, Levkau B. et al. Current status and future applications of cardiac receptor imaging with positron emission tomography. Nucl Med Commun 2002; 23: 113-5.
- 36 Shiue C, Pleus RC, Shiue GG. et al. Synthesis and biological evaluation of [11C]MK-912 as an alpha2-adrenergic receptor radioligand for PET studies. Nucl Med Biol 1998; 25: 127-33.
- 37 Soloviev DV, Matarrese M, Moresco RM. et al. Asymmetric synthesis and preliminary evaluation of (R)- and (S)-[11C]bisoprolol, a putative beta1-selective adrenoceptor radioligand. Neurochem Int 2001; 38: 169-80.
- 38 Steinfath M, Geertz B, Schmitz W. et al. Distinct downregulation of cardiac 1 and 2 adrenoceptors in different human heart diseases. Naunyn Schmiedeberg’s Arch Pharmacol 1991; 343: 217-20.
- 39 Steinfath M, Lavicky J, Schmitz W. et al. Changes in cardiac b-adrenoceptors in human heart diseases: relationship to the degree of heart failure and further evidence for etiology-related regulation of b1 and b2 subtypes. J Cardiothora. Vasc Anesth 1993; 7: 668-73.
- 40 Steinfath M, Lavicky J, Schmitz W. et al. Regional distribution of 1- and 2-adrenoceptors in the failing and nonfailing human heart. Eur J Clin Pharamcol 1992; 42: 607-12.
- 41 Stiles GL, Taylor S, Lefkowitz RJ. Human cardiac -adrenergic receptors: subtype heterogeneity delineated by direct radioligand biding. Life Sci 1983; 33: 467-73.
- 42 Syrota A. Receptor binding studies of the living heart. New Concepts Cardiac Imaging 1988; 4: 141-61.
- 43 Tsien RW. Cyclic AMP and contractile activity in the heart. Adv Cyclic Nucl Res 1977; 8: 363-420.
- 44 Valette H, Dolle F, Guenther I. et al. Preliminary evaluation of 2-[4-[3-tert-butylamino)-2-hydroxypropoxy]phenyl]-3-methyl-6-methoxy-4(3H)-quinazolinone ([+/-]HX-CH 44) as a selective beta1-adrenoceptor ligand for PET. Nucl Med Biol 1999; 26: 105-9.
- 45 Van Waarde A, Elsinga PH, Brodde OE. et al. Myocardial and pulmonary uptake of S-1’-[18F]fluorocarazolol in intact rats reflects radioligand binding to b-adrenoceptors. Eur J Pharmacol 1995; 272: 159-68.
- 46 Van Waarde A, Meeder JG, Blanksma PK. et al. Suitability of CGP 12177 and CGP 26505 for quantitative imaging of beta-adrenoceptors. Int J Rad Appl Instrum B 1992; 19: 711-8.
- 47 Van Waarde A, Visser TJ, Elsinga PH. et al. Imaging beta-adrenoceptors in the human brain with (S)-1’-[18F]fluorocarazolol. J Nucl Med 1997; 38: 934-9.
- 48 Visser TJ, van Waarde A, Doze P. et al. Characterization of 2-adrenoceptors, using the agonist [11C]formoterol and positron emission tomography. Eur J Pharmacol 1998; 361: 35-41.
- 49 Wichter T, Schäfers M, Rhodes CG. et al. Abnormalities of cardiac sympathetic innervation in arrhythmogenic right ventricular cardiomyopathy: quantitative assessment of presynaptic norepinephrine reuptake and postsynaptic beta-adrenergic receptor density with positron emission tomography. Circulation 2000; 101: 1552-8.
- 50 Zipes DP. Sympathetic stimulation and arrhythmias. N Engl J Med 1991; 325: 656-7.