IN-VIVO BINDING, PHARMACOKINETICS AND METABOLISM OF THE SELECTIVE M(2) MUSCARINIC ANTAGONISTS [H-3]AF-DX-116 AND [H-3]AF-DX-184 IN THE ANESTHETIZED RAT

The pharmacokinetics, in vivo binding and metabolism of two M(2) musca rinic receptor antagonists, [H-3]AF-DX 116 and [H-3]AF-DX 384, were st udied in anesthetized rats, which received either the tracer alone or following a saturating injection of atropine. Both radioligands were c leared from the circulation with distribution half lives of 17 and 14 sec and elimination half-lives of 17 and 40 min for [H-3]AF-DX 116 and [H-3]AF-DX 384, respectively. A radioactive distribution, predominant in peripheral organs when compared to brain, was found at each time s tudied after tracer injection. Atropine displaceable tracer uptake was evidenced at 20-40 min in brain (31%), submandibular glands (26%), sp leen (37%) and notably heart (55%) for [H-3]AF-DX 116 but only in hear t (50%) for [H-3]AF-DX 384 at 10-20 min. Regional brain sampling revea led a relatively uniform distribution of [H-3]AF-DX 384 and a -45% atr opine saturation effect (i.e., specific binding) in the thalamus 20 mi n after injection. Sequential thin layer chromatographic studies perfo rmed on tissue extracts demonstrated the rapid appearance of labeled m etabolites of both radiotracers in brain (but less so in liver) and es pecially in cardiac tissues, where almost 70% of total radioactivity s till corresponded to authentic tracer 40 min after injection. Thus, ba sed on their low blood-brain barrier permeability and the high presenc e of labeled metabolites in the central nervous system, AF-DX 116 and AF-DX 384 might be more helpful in the study of M(2) muscarinic recept ors present in heart rather than brain. Labeled with positron emitters , these M(2) antagonists might be applicable to the pathophysiological study of disease states, such as cardiomyopathies.