Kinetics of in vivo binding of antagonist to muscarinic cholinergic receptor in the human heart studied by positron emission tomography.

Positron Emission Tomography (PET) was used to analyse in vivo antagonist binding to human myocardial muscarinic cholinergic receptor. The methiodide salt of the muscarinic antagonist, quinuclidinyl benzilate (MQNB), was labeled with the positron emitter, Carbon-11, and injected intravenously to 8 normal subjects. 11C-MQNB concentration was determined in vivo in the ventricular septum from 40 cross-sectional images acquired at the same transverse level over a period of 70 minutes. In 4 subjects, various amounts of unlabeled atropine were rapidly injected at 20 minutes to study whether atropine competitively inhibited MQNB. The kinetics of binding of 11C-MQNB were not the same in vivo and in vitro. The apparent dissociation rate of 11C-MQNB in vivo was much slower (by 1 to 2 orders of magnitude) than that observed in vitro with 3H-QNB. After atropine injection, 11C-MQNB dissociated from its binding sites at a rate that apparently depended on the amount of atropine present. 11C-MQNB kinetics were analysed with a mathematical model which assumes the existence of a boundary layer containing free ligand in the vicinity of the binding sites. The dissociation rate of the radioligand depends on the probability of its rebinding to a free receptor site.