Acute effects of physostigmine and galantamine on the binding of [¹⁸F]fluoro-A-85380: A PET study in monkeys

Abstract

2-[18F]fluoro-3-[2S-2-azetidinylmethoxy]pyridine ([18F]fluoro-A-85380) is an alpha4beta2 subtype selective nicotinic cholinergic agonist with potential suitability for studying changes in endogenous acetylcholine synaptic concentration. Physostigmine, a potent AChE inhibitor, and galantamine, an allosteric modulator of nAChRs, are widely used for the treatment of Alzheimer's disease. Before studying patients with this neurodegenerative disease, positron emission tomography (PET) studies in monkeys were performed to assess the impact of these two compounds on the radiotracer distribution volumes. Physostigmine was administered i.v. at two dosages: 150 microg/kg/h and 37.5 microg/kg/h for 160 min. Galantamine was administered i.v. at two dosages: 2 or 4 mg over 20 min. For PET data analysis, a model with one tissue (radioactivity of the parent compound in plasma and radioactivity in brain tissue) compartment was chosen because reliable parameter estimates could not be obtained with a more complex model. The higher dose of physostigmine produced a 40%, 23%, and 30% reduction of distribution volumes in the putamen, the temporal, and frontal cortices, respectively. The lower dose of physostigmine produced a reduction of 33%, 31%, and 24% in the same structures, respectively. Galantamine (4 mg or 2 mg) produced no significant change of distribution volumes in the basal ganglia, the temporal and frontal cortex. The effects of physostigmine, a more potent AChE inhibitor than galantamine, could be interpreted as a desensitization of nAChRs, due to a prolonged exposure to high synaptic concentration of acetylcholine or as a competition with acetylcholine.

A‐85380: A Pharmacological Probe for the Preclinical and Clinical Investigation of the α4β2 Neuronal Nicotinic Acetylcholine Receptor

“…One of the first described was 2-[ 18 F]F-A-85380, a fluoro derivative of A-85380, as a potential positron emission tomography ligand (PET; 18). It has been shown to cross the blood brain barrier (8) and to bind competitively to nAChRs as its specific binding can be displaced by cytisine (8,16) and by endogenous acetylcholine (18,53). More specifically, it binds selectively to á 4 â 2 , and not to á 7 or 5-HT 3 , receptors (18).…”

“…More specifically, it binds selectively to á 4 â 2 , and not to á 7 or 5-HT 3 , receptors (18). The ability to quantitate nAChRs in vivo using 2-[ 18 F]F-A-85380 has been shown in rats, pigs, rhesus monkeys, baboons, and humans (8,9,16,18,28,53). In addition to the demonstration of specific binding to á 4 â 2 nAChRs in vivo, 2-[ 18 F]F-A-85380 has been demonstrated to be safe, allowing its use in the investigation of disease states in preclinical species and in human (37,55,57).…”

Radiosynthesis of 2-exo-(2′-[18F]Fluoro-3′-(4-fluorophenyl)-pyridin-5′-yl)-7-azabicyclo[2.2.1]heptane ([18F]F2PhEP), a potent epibatidine-based radioligand for nicotinic acetylcholine receptor PET imaging

“…[13][14][15][16][17] It also displays a safe profile -low toxicity, 12,18 no mutagenicity 12,18 and acceptable effective dose equivalent to the patient in dosimetric studies 12,19,20 -for its use in humans. 21,22 On the other hand, 2-[ 18 F]F-A-85380 is a relatively stronghydrophilic derivative displaying rather slow brain kinetics.…”

News and views on in-vivo imaging of neurotransmission using PET and MRI

“…Thus, physostigmine infusion leads to significant reductions of 2-[ 18 F]FA 91 , (−)-[ 18 F]flubatine 92 , and [ 18 F]nifene binding 93 . These preclinical investigations suggest that sensitivity for measuring changes of extracellular acetylcholine could feasible with all these tracers.…”