High non-specific binding of the β1-selective radioligand 2-125I-ICI-H

B. Riemann; M. P. Law; K. Kopka; St. Wagner; S. Luthra; V. W. Pike; J. Neumann; U. Kirchhefer; W. Schmitz; O. Schober; M. Schäfers

doi:10.1055/s-0038-1625187

Nuklearmedizin - NuclearMedicine, Inhaltsverzeichnis

Nuklearmedizin 2003; 42(04): 173-180
DOI: 10.1055/s-0038-1625187

Original Article

Schattauer GmbH

High non-specific binding of the β₁-selective radioligand 2-¹²⁵I-ICI-H

Hohe unspezifische Bindung des β₁-selektiven Radioliganden 2-¹²⁵I-ICI-H

Autoren

B. Riemann

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

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

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

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

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

³Imaging Research Solutions Limited, Cyclotron Building (Head: Prof. Dr. J. Thornback), Hammersmith Hospital, London, United Kingdom
V. W. Pike

⁴Molecular Imaging Branch, National Institute of Mental Health, National Institute of Health, Bethesda, MD, USA
J. Neumann

⁵Institute of Pharmacology and Toxicology (Head: Prof. Dr. W. Schmitz), Münster University, Germany
U. Kirchhefer

⁵Institute of Pharmacology and Toxicology (Head: Prof. Dr. W. Schmitz), Münster University, Germany
W. Schmitz

⁵Institute of Pharmacology and Toxicology (Head: Prof. Dr. W. Schmitz), Münster University, Germany
O. Schober

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

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

Abstract

Summary:

Aim: As results of cardiac biopsies suggest, myocardial β₁-adrenoceptor density is reduced in patients with chronic heart failure. However, changes in cardiac β_2-adrenoceptors vary. With suitable radiopharmaceuticals single photon emission computed tomography (SPECT) and positron emission tomography (PET) offer the opportunity to assess β-adrenoceptors non-invasively. Among the novel racemic analogues of the established β₁-selective adrenoceptor antagonist ICI 89.406 the iodinated 2-I-ICI-H showed high affinity and selectivity to β₁-adrenoceptors in murine ventricular membranes. The aim of this study was its evaluation as a putative sub-type selective β₁-adrenergic radioligand in cardiac imaging. Methods: Competition studies in vitro and in vivo were used to investigate the kinetics of 2-I-ICI-H binding to cardiac β-adrenoceptors in mice and rats. In addition, the radiosynthesis of 2-¹²⁵I-ICI-H from the silylated precursor 2-SiMe₃-ICI-H was established. The specific activity was 80 GBq/µmol, the radiochemical yield ranged from 70 to 80%.

Results: The unlabelled compound 2-I-ICI-H showed high β₁-selectivity and -affinity in the in vitro competition studies. In vivo biodistribution studies apparently showed low affinity to cardiac β-adrenoceptors. The radiolabelled counterpart 2-¹²⁵I-ICI-H showed a high degree of non-specific binding in vitro and no specific binding to cardiac β₁-adrenoceptors in vivo. Conclusion: Because of its high non-specific binding 2-¹²⁵I-ICI-H is no suitable radiotracer for imaging in vivo.

Zusammenfassung:

Ziel: Bei chronischer Herzinsuffizienz existieren bioptische Hinweise auf eine Verminderung der kardialen β₁-Adrenozeptoren bei variablen Ergebnissen für die β₂-Adrenozeptoren. SPECT und PET ermöglichen mit geeigneten Radiopharmaka, die β-Adrenozeptoren nicht invasiv zu quantifizieren. Von den neu synthetisierten racemischen Derivaten des β₁-selektiven AdrenozeptorAntagonisten ICI 89.406 zeigte in Untersuchungen an Membranpräparaten des Mausventrikels das iodierte Derivat 2-I-ICI-H eine hohe β₁-Affinität und -Selektivität. Ziel dieser Studie war die Evaluation von 2-I-ICI-H als möglichen subtypselektiven β₁-Adrenozeptorradioliganden der kardialen Bildgebung. Methode: Die Bindungskinetik des 2-I-ICI-H an β-Adrenozeptoren wurde in vitro und in vivo an Mäusen und Ratten in Kompetitionsstudien untersucht. Die Radiosynthese von 2-¹²⁵I-ICI-H aus dem silylierten Vorläufer 2-SiMe₃-ICI-H wurde etabliert (spezifische Aktivität: 80 GBq/µmol; radiochemische Ausbeute: 70-80%). Ergebnisse: Nicht radioaktives 2-I-ICI-H zeigte in In-vitro-Kompetitionsstudien eine hohe β₁-Selektivität und -Affinität. Allerdings ergaben In-vivo-Biodistributionsstudien eine geringe apparente Affinität zu den kardialen β-Adrenozeptoren. Die entsprechende radioiodierte Verbindung (2-¹²⁵I -ICI-H) wurde in vitro fast und in vivo als völlig unspezifisch an kardiale β₁-Adrenozeptoren gebunden. Schlussfolgerung: Die Vorläufersubstanz 2-SiMe₃-ICI-H wurde mit Iod-125 markiert, um den β₁-Adrenozeptorantagonisten 2-¹²⁵I-ICI-H zu erhalten, der wegen seiner unspezifischen Bindung in vivo als Radiotracer ungeeignet scheint.

Key words:

SPECT - PET - β₁-adrenoceptor radioligands - cardiac imaging

Schlüsselwörter:

SPECT - PET - β₁-Adrenozeptor Radioliganden - kardiale Bildgebung

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Referenzen

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