Nicotinic acetylcholine receptors (nAChRs) have been implicated in a number of neurological disorders. 5-Iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) is a novel nAChR marker, binding predominantly to the alpha4beta2 subtype. This in vitro autoradiography study describes the distribution of 5-[I-125]-A-85380 binding in post-mortem brain tissue from normal elderly individuals and from cases with age-associated dementias of both neurodegenerative and vascular types. The binding distribution of 5-[(125I)]-A-85380 in normal brain tissue was found to be consistent with the reported distribution of other high-affinity nicotinic ligands. In addition to high thalamic and moderate striatal and temporal cortex density, moderate 5-[I-125]-A-85380 binding was also seen in white matter tracts in cingulate, occipital, and temporal areas, indicating the presence of nAChRs along nerve fiber tracts, which has not been reported in other high-affinity nicotinic agonist distribution studies. In Parkinson’s disease (PD), loss of striatal 5-[I-125]-A-85380 binding closely parallels the loss of nigrostriatal dopaminergic markers previously observed. In dementia with Lewy bodies (DLB) reduced striatal 5-[I-125]-A-85380 binding density, comparable to that in PD, may be a marker of early degeneration in nigrostriatal inputs, while in Alzheimer’s disease (AD) reduced striatal 5-[I-125]-A-85380 binding could be related to reduced cortical inputs. The reductions of nAChRs seen in AD, DLB, and PD were not apparent in vascular dementia (VaD). In conclusion, 5-1-A-85380 is clearly a useful ligand for both in vitro and in vivo single photon emission tomography human studies investigating disease symptoms and progression, response to acetylcholinesterase-inhibiting drugs and in differentiating primary degenerative dementia from VaD.