Positron Emission Tomography Study In Monkeys Research Articles

Blood–brain barrier permeability of ginkgolide: Comparison of the behavior of PET probes 7α-[18F]fluoro- and 10-O-p-[11C]methylbenzyl ginkgolide B in monkey and rat brains

The blood–brain barrier permeability of ginkgolide B was examined using positron emission tomography (PET) probes of a 18F-incorporated ginkgolide B ([18F]-2) and a 11C-incorporated methylbenzyl-substituted ginkgolide B ([11C]-3). PET studies in monkeys showed low uptake of [18F]-2 into the brain, but small amounts of [11C]-3 were accumulated in the parenchyma. Furthermore, when cyclosporine A was preadministered to rats, the accumulation of [18F]-2 in the rat brain did not significantly change, however, the accumulation of [11C]-3 was five times higher than that in the control rat. These results provide effective approaches for investigating the drug potential of ginkgolides.

Differential effects of paroxetine on raphe and cortical 5-HT1A binding: A PET study in monkeys

Positron emission tomography (PET) ligands that are sensitive to transient changes in serotonin (5-HT) concentration are desirable for studies of neuropsychiatric diseases. Few studies, however, have sought to demonstrate that variations in 5-HT concentration can be closely tracked with available serotonergic ligands. Microdialysis studies in rats have shown a maximal increase in 5-HT concentration in raphe nuclei after systemic infusion of selective serotonergic re-uptake inhibitors (SSRIs). We performed PET scans with [18F]FPWAY, an intermediate-affinity antagonist of 5-HT1A receptors, in 4 anesthetized rhesus monkeys in control studies and after systemic paroxetine administration (5 mg/kg, i.v.). In addition, a paired [11C]DASB study revealed that this paroxetine regimen produced an occupancy of 54–83% of the serotonin transporters. According to the conventional receptor competition model, increased 5-HT concentration produces decreased binding of the radioactive ligand. Over a 3-h period following paroxetine infusion, a progressively increasing reduction (ranging from 8 ± 6% to 27 ± 10%) of [18F]FPWAY-specific binding was found in the raphe nuclei. This result is interpreted as an SSRI-induced increase in 5-HT concentration, potentially combined with reduced binding to internalized 5-HT1A receptors. In addition, a transient (1 h) increase in cerebral cortical binding was observed, attributed primarily to a reduction in cortical 5-HT due to the effects of raphe autoreceptor inhibition. This study is the first demonstration of the feasibility of quantifying dynamic changes in 5-HT neurotransmission in the raphe and the cortex with PET. These results lend promise to the use of these serotonergic neuroimaging techniques to study neuropsychiatric disorders.

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

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.

Long-lasting occupancy of central nicotinic acetylcholine receptors after smoking: a PET study in monkeys.

The aim of this study was to compare the degree of occupancy of central nicotinic acetylcholine receptors (nAChR) in isoflurane anaesthetized baboon brain following inhalation of tobacco smoke (one cigarette containing 0.9 mg nicotine) or i.v. nicotine (0.6 mg i.v.). [18F]Fluoro-A-85380 and positron emission tomography (PET) were used to assess the distribution volumes (DV) of the radiotracer in selected brain areas using a one-compartment model. Eighty minutes after nicotine i.v., DV was reduced by 50 and 66% in the thalamus and putamen, respectively. Six hours after nicotine, a reduction in DV (27% in the thalamus) was still observed. Eighty minutes after inhalation of tobacco smoke, DV was decreased by 52 and 65% in the thalamus and putamen, respectively. Previous PET experiments have demonstrated a short-lasting interaction of [11C]nicotine with nAChRs. Thus, we hypothesized that a metabolite of nicotine with high affinity and long half-live (several hours) could bind at nAChRs. Eighty minutes after a high dose of nornicotine (0.5 mg i.v.), DV was reduced by 53 and 31% in thalamus and putamen, respectively. No significant effect was observed following 0.15 mg nornicotine. Therefore, nornicotine could contribute to the long-lasting occupancy of central nAChRs after smoking.