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 beta-blocker inhibiting both beta(1)- and beta(2)-adrenoreceptors (beta-ARs), various selective beta(1)-blockers, including bisoprolol, have been developed to overcome disadvantages associated with beta(2)-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 beta-blocker toward beta(1)-AR, as the heart and peripheral smooth muscles demonstrate distinct populations of beta(1)- and beta(2)-ARs. Biodistribution of F-18-labeled bisoprolol (1, [F-18]bisoprolol) showed the retention of its uptake in the heart compared with other beta-AR-rich organs at late time points post-injection. The competitive blocking assay using unlabeled bisoprolol exhibited no inhibition of [F-18]bisoprolol uptake in any organ but exhibited significantly rapid loss of radioactivity between two different time points in beta(1)-AR-rich organs such as the heart and brain. Furthermore, the organ-to-blood ratio revealed the slow excretion and better accumulation of [F-18] 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 beta(1)-ARs in the heart and provided the possibility of PET as an in vivo technique for evaluating drug selectivity.

Automated summary

The selectivity of drugs towards different isoforms of target proteins is crucial in toxicology. This study used PET to investigate the in vivo distribution and selectivity of bisoprolol as a selective beta-blocker targeting beta(1)-AR, providing insightful evidence and demonstrating the potential of PET as a tool for evaluating drug selectivity.