Kinetic analysis of muscarinic receptors in human brain and salivary gland in vivo

Y. Hiramatsu, W. C. Eckelman, J. A. Carrasquillo, R. S. Miletich, I. H. Valdez, R. H. Kurrasch, A. A. Macynski, C. H. Paik, R. D. Neumann and B. J. Baum Clinical Investigations and Patient Care Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892, USA. Previous studies in rats have suggested that the muscarinic acetylcholine receptor (mAChR) antagonist (S)-3-quinuclidinyl-(S)-4-[123I]iodobenzilate [(SS)-IQNB] may be useful for the in vivo evaluation of mAChRs in humans as a control for the higher-affinity compound (RR)-IQNB. We have directly tested this hypothesis and examined the distribution of mAChRs in brain regions and parotid glands of healthy human volunteers in vivo using (RR)- and (SS)-IQNB (relatively high- and low-affinity antagonists, respectively), planar imaging, and pharmacokinetic analysis. This is the first in vivo study of mAChRs in humans that has employed stereoisomeric ligands and metabolic analysis to determine specific receptor binding. We observed that (SS)-IQNB showed much faster clearance from blood than (RR)-IQNB and different metabolite profiles. Also, the transport kinetics of the enantiomers were different. The estimated binding potential (approximately Bmax/Kd) of (RR)-IQNB was highest in two cortical regions, intermediate in parotid gland, and lowest in cerebellum. The aggregate results show that in humans (SS)-IQNB does not act as an ideal general probe to measure the nonspecific IQNB distribution. However, (RR)-IQNB does appear to have value when used for studies of human brain mAChRs.