Non-Invasive Molecular Imaging of β-Adrenoceptors In Vivo: Perspectives for PET-Radioligands

Abstract

Recently, the spectrum of molecular imaging devices such as positron emission tomography (PET) was further expanded by the now clinically available combined imaging modalities such as PET-CT and the preclinically used small animal PET scanners. These are powerful tools that can bridge the gap between preclinical and clinical evaluation studies of new radiotracers for molecular imaging of healthy and diseased states in vivo. The beta-adrenoceptor (beta-AR) radioligands discussed in this review represent a class of molecular probes for the non-invasive in vivo assessment of beta-AR density eg. in the heart with PET. The beta-AR radioligands (S)-[11C]CGP 12177 (1) or (S)-[11C]CGP 12388 (2) are currently investigated in clinical studies with PET. Additionally, subtype-selective beta1-AR radioligands are used in preclinical research which show potential for the diagnostics of the "beta1-AR organ" as such the heart can be defined. Non-invasive quantification of beta-ARs could facilitate the accurate choice and control of therapeutic interventions. Here we summarize the state-of-the-art of the radiochemistry of radioactive beta-AR radioligands.

Synthesis of an18F-labelled high affinityβ1-adrenoceptor PET radioligand based on ICI 89,406

“…[35][36][37][38] Compounds 4a-b were converted into the corresponding Scheme 1. Lead structure ICI 89,406 and its radiolabelled derivatives [25][26][27][28][29] did not succeed and provided, besides a low yield of urea 8c (11%), mainly polymeric side products (Scheme 3). Finally, the bromide 8c was converted with silver p-toluenesulphonate into the tosylate precursor 8d in 46% yield (Scheme 2).…”

“…[30][31][32] ICI 89,406 was chosen as the lead structure for the development of new b 1 -selective AR radiotracers for application in nuclear medical imaging. After identification of several ICI 89,406 derivatives with high b 1 -AR binding affinity 33 [27][28][29] At present this radioligand is being evaluated in vivo. In a further step we aimed at the development of an 18 F-labelled ICI 89,406 derivative due to the superior physical decay characteristics (longer half-life, shorter average positron range) of 18 …”

Molecular imaging targets of cardiac remodeling

“…Imaging cardiac sympathetic innervation has found clinical application in the evaluation of chemotherapy-related LV dysfunction, diabetic cardiomyopathy, prognostication and assessment of risk of sudden death in patients with HF, and evaluation of the response to pharmacologic interventions including treatment with inhibitors of angiotensin or the β-adrenergic systems [44]. Attempts are under way for experimental in vivo evaluation of an 11 C-labeled subtype-selective β 1 -adrenergic PET radioligand [45].…”

N-Isopropylbenzamide

“…For related literature, see: Clayden et al (2006); Kopka et al (2005); Smart (2001); Van Waarde et al (2004); ; Stephenson, van Oosten et al (2008).…”