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The precise effects of normal aging on the cholinergic system are unknown, as both in vitro and PET studies have shown conflicting results. In vivo determination of muscarinic receptor distribution and density has been hampered by both poor subtype selectivity and/or blood–brain barrier permeability of known ligands. Previous in vitro and in vivo work with the F-18 labeled muscarinic agonist, 3-(3- (3-[18F]Flouropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine (18FP-TZTP) suggested the use of 18FP-TZTP to selectively quantify M2 receptors in humans. In this study, we used 18FP-TZTP to infer M2 receptor avidity in the brains of 15 healthy younger subjects (mean age = 28.3 ± 5.5 years) and 20 healthy older subjects (mean age = 62.1 ± 7.7 years). Corrections for subject motion during the 120-min acquisition and partial voluming (PVC) were performed. A one-tissue compartment model was used to estimate the volumes of distribution (VT) of 18FP-TZTP. Within both groups of subjects, volumes of distribution (K1/k2) in cortical, subcortical, and cerebellar areas were consistent with M2 receptor topography. Compared to younger subjects older subjects had significantly higher means and standard deviations for the volumes of distribution of 18FP-TZTP throughout much of the cerebellum, cortex, and subcortex (Global Gray VT = 742 ± 163 in older subjects and 645 ± 74 in younger subjects, P < 0.03). Across all subjects 18FP-TZTP, regional, and Global Gray distribution volumes were significantly correlated to age (Global Gray VT, r = 0.41, P < 0.01). A lower concentration of acetylcholine in the synapse of some older subjects is one possible explanation for the data. Synapse 48:39–44, 2003. Published 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]