Bisoprolol-based 18F-PET tracer: Synthesis and preliminary in vivo validation of β1-blocker selectivity for β1-adrenergic receptors in the heart

The selectivity of a drug toward various isoforms of the target protein family is important in terms of toxicology. Typically, drug or candidate selectivity is assessed by in vitro assays, but in vivo investigations are currently lacking. Positron emission tomography (PET) allows the non-invasive determination of the in vivo distribution of a radiolabeled drug, which can provide in vivo data regarding drug selectivity. Since the discovery of propranolol, a non-selective β-blocker inhibiting both β1- and β2-adrenoreceptors (β-ARs), various selective β1-blockers, including bisoprolol, have been developed to overcome disadvantages associated with β2-AR inhibition. As a proof of concept, we performed an in vivo PET study to understand the selectivity and efficacy of bisoprolol as a selective β-blocker toward β1-AR, as the heart and peripheral smooth muscles demonstrate distinct populations of β1- and β2-ARs. Biodistribution of 18F-labeled bisoprolol (1, [18F]bisoprolol) showed the retention of its uptake in the heart compared with other β-AR-rich organs at late time points post-injection. The competitive blocking assay using unlabeled bisoprolol exhibited no inhibition of [18F]bisoprolol uptake in any organ but exhibited significantly rapid loss of radioactivity between two different time points in β1-AR-rich organs such as the heart and brain. Furthermore, the organ-to-blood ratio revealed the slow excretion and better accumulation of [18F]bisoprolol inside the heart. Collectively, the ex vivo biodistribution and blocking study presented insightful evidence to better comprehend the in vivo distribution pattern of bisoprolol as a selective inhibitor targeting β1-ARs in the heart and provided the possibility of PET as an in vivo technique for evaluating drug selectivity.