Ligands for in vivo imaging of nicotinic receptor subtypes in Alzheimer brain.
The neuronal nicotinic acetylcholine receptors (nAChR) are involved in functional processes in brain including cognitive function and memory. A severe loss of the nAChRs has been detected in brain of patients with Alzheimer's disease (AD). There is a great interest to image nAChRs noninvasive for detection of receptor impairments even at a presymptomatic stage of AD as well for monitoring outcome of drug treatment. (S) [11C]Nicotine, has so far been the only nAChR ligand used in positron emission tomography (PET) studies for visualizing nAChRs in human brain. In order to develop PET/SPECT nAChRs ligands for detection of subtypes of nAChRs nicotine analogues, epibatidine and A-85380 compounds have been characterized in vitro and investigated in vivo. Epibatidine and A-85380 have been found to have higher specific signals and more favorable kinetic parameters than nicotine and its analogues. The epibatidine and A-85380 compounds can also be radiolabeled with high specific radioactivity, show affinities for the nAChRs in the pM range and readily cross the blood-brain barrier. In addition they reversibly bind to the nAChRs and show low non-specific binding and moderately fast metabolism. Due to a probably high alpha4beta2 nAChR selectivity combined with low toxicity, the A-85380 analogs presently seem to be the most promising nAChR ligand imaging of subtypes of nAChRs in human brain.
PET-Center/Institute of Chemistry, Uppsala University, Sweden.
W
W
Sihver
B
B
Långström
A
A
Nordberg
D000544:Alzheimer Disease / Q000503:physiopathology*; D000818:Animals; D001384:Azetidines / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D018678:Cholinergic Agents / Q000493:pharmacokinetics; D006801:Humans; D008024:Ligands; D011323:Primates; D011725:Pyridines / Q000493:pharmacokinetics; D051381:Rats; D011978:Receptors, Nicotinic / Q000032:analysis*; D014055:Tomography, Emission-Computed
C104288:A 85380; D001384:Azetidines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018678:Cholinergic Agents; D008024:Ligands; D011725:Pyridines; D011978:Receptors, Nicotinic; C082748:epibatidine