Radioligands for imaging myocardial α- and β-adrenoceptors

B. Riemann; M. Schäfers; M. P. Law; T. Wichter; O. Schober

doi:10.1055/s-0038-1623898

Nuklearmedizin - NuclearMedicine, Table of Contents

Nuklearmedizin 2003; 42(01): 4-9
DOI: 10.1055/s-0038-1623898

Original Article

Schattauer GmbH

Radioligands for imaging myocardial α- and β-adrenoceptors^[*]

Radioliganden für die Bildgebung kardialer α- und β-Adrenozeptoren

B. Riemann

¹Department of Nuclear Medicine (Head: Prof. Dr. Dr. O. Schober)

,

M. Schäfers

¹Department of Nuclear Medicine (Head: Prof. Dr. Dr. O. Schober)

,

M. P. Law

²MRC Clinical Sciences Centre, Imperial College School of Science, Technology and Medicine (Head: Prof. Dr. P. G. Camici) Hammersmith Hospital, London, UK

,

T. Wichter

³Cardiology and Angiology (Head: Prof. Dr. G. Breithardt), Münster University, Germany

,

O. Schober

¹Department of Nuclear Medicine (Head: Prof. Dr. Dr. O. Schober)

› Author Affiliations

Abstract

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-, β_4-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.

Keywords

Adrenoceptors - myocardium - PET

Schlüsselwörter

Adrenozeptoren - Myokard - PET

Full Text

References

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Radioligands for imaging myocardial α- and β-adrenoceptors[*]

Radioligands for imaging myocardial α- and β-adrenoceptors^[*]