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

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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