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(R)-[11C]verapamil is a radiotracer widely used for the evaluation of the P-glycoprotein (P-gp) function at the blood–brain barrier (BBB). Several studies have evaluated the pharmacokinetics of (R)-[11C]verapamil in rats and humans under different conditions. However, to the best of our knowledge, the pharmacokinetics of (R)-[11C]verapamil have not yet been evaluated in nonhuman primates. Our study aims to establish (R)-[11C]verapamil as a reference P-gp tracer for comparison of a newly developed P-gp positron emission tomography (PET) tracer in a species close to humans. Therefore, the study assesses the kinetics of (R)-[11C]verapamil and evaluates the effect of scan duration and P-gp inhibition on estimated pharmacokinetic parameters. Three nonhuman primates underwent two dynamic 91 min PET scans with arterial blood sampling, one at baseline and another after inhibition of the P-gp function. The (R)-[11C]verapamil data were analyzed using 1-tissue compartment model (1-TCM) and 2-tissue compartment model fits using plasma-corrected for polar radio-metabolites or non-corrected for radio-metabolites as an input function and with various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (SE %) of the estimated parameters. 1-TCM was selected as the model of choice to analyze the (R)-[11C]verapamil data at baseline and after inhibition and for all scan durations tested. The volume of distribution (VT) and the efflux constant k2estimations were affected by the evaluated scan durations, whereas the influx constant K1estimations remained relatively constant. After P-gp inhibition (tariquidar, 8 mg/kg), in a 91 min scan duration, the whole-brain VTincreased significantly up to 208% (p< 0.001) and K1up to 159% (p< 0.001) compared with baseline scans. The k2values decreased significantly after P-gp inhibition in all the scan durations except for the 91 min scans. This study suggests the use of K1, calculated with 1-TCM and using short PET scans (10 to 30 min), as a suitable parameter to measure the P-gp function at the BBB of nonhuman primates.

[18F]MC225 has been developed as a weak substrate of P-glycoprotein (P-gp) aimed to measure changes in the P-gp function at the blood–brain barrier with positron emission tomography. This study evaluates [18F]MC225 kinetics in non-human primates and investigates the effect of both scan duration and P-gp inhibition. Three rhesus monkeys underwent two 91-min dynamic scans with blood sampling at baseline and after P-gp inhibition (8 mg/kg tariquidar). Data were analyzed using the 1-tissue compartment model (1-TCM) and 2-tissue compartment model (2-TCM) fits using metabolite-corrected plasma as the input function and for various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (%) of the estimated parameters. For the 91-min scan duration, the influx constant K1increased by 40.7% and the volume of distribution (VT) by 30.4% after P-gp inhibition, while the efflux constant k2did not change significantly. Similar changes were found for all evaluated scan durations. K1did not depend on scan duration (10 min—K1= 0.2191 vs 91 min—K1= 0.2258), while VTand k2did. A scan duration of 10 min seems sufficient to properly evaluate the P-gp function using K1obtained with 1-TCM. For the 91-min scan, VTand K1can be estimated with a 2-TCM, and both parameters can be used to assess P-gp function.

In the development of an efficient 18F‐labeling method for the synthesis of PET tracers, it is essential not only to improve the efficiency of [18F]fluorine incorporation into a carrier but also to minimize non‐radioactive side products from the precursor. Highly reactive sulfonate esters are promising precursors for 18F‐nucleophilic fluorination under mild conditions. However, the expected labeling efficiency from the precursor is often hampered by its competitive degradation due to coexisting bases during 18F‐fluorination. In this report, we designed a 2‐methyl‐6‐nitrobenzenesulfonate (2‐MeNs) ester as a precursor for 18F‐fluorination, in which the methyl group suppresses hydrolysis of the sulfonate ester via steric hindrance. An increase in labeling efficiency in the 18F‐labeling of a neopentyl labeling group was observed for the neopentyl 2‐MeNs ester compared with that of the 2‐nitrobenzenesulfonate ester. Ultimately, we achieved the automated synthesis of an 18F‐labeled amino acid using a neopentyl labeling group by using a 2‐MeNs ester as a precursor. Substituting the o‐position of a sulfonate ester as a precursor for 18F fluorination allows the suppression of S‐substitution without significantly reducing the reactivity of C‐substitution. This results in an efficient synthesis of neopentyl 18F‐labeled amino acids.

Three patients with neurological disorders (cerebral infarction, progressive multifocal leukoencephalopathy, and multiple sclerosis) underwent 18F-THK5351 and 11C-L-deprenyl PET on the same day to visualize lesions undergoing astrogliosis by measuring MAO-B activity. BPNDmap and SUV image with 18F-THK5351 as well as Kimap, Ki/K1map and SUV image with 11C-L-deprenyl were created. 18F-THK5351 BPNDmaps and SUV images clearly identified the lesions undergoing astrogliosis. 11C-L-deprenyl Ki/K1maps were close to 18F-THK5351 images, but very noisy. Kimaps and SUV images were likely affected by the effect of blood flow. Hence, 18F-THK5351 is superior to 11C-L-deprenyl for visualizing lesions undergoing astrogliosis.

A 26-year-old woman with relapsing-remitting multiple sclerosis (MS) underwent 18F-THK5351 PET during a remission period. PET imaging showed that small regions with elevated uptake of 18F-THK5351 were scattered in the brain and that the foci of 18F-THK5351 accumulations corresponded anatomically to MS plaques identified by MRI. Because 18F-THK5351 binds to monoamine oxidase B highly expressed in astrocytes, 18F-THK5351 accumulates in lesions undergoing astrogliosis. Hence, elevated uptake of 18F-THK5351 in the present case can represent ongoing astrogliosis in inactive MS lesions (plaques).

An 86-year-old woman with cognitive impairment and left hemiparesis underwent 18F-THK5351 PET 4 months before her death. In addition to “normal” off-target binding in the basal ganglia, abnormal accumulation was observed along the pyramidal tract and around the right basal ganglia as ring-shaped uptake that overlapped a gadolinium-enhanced lesion. Postmortem pathological examination revealed that she had glioblastoma multiforme with associated gliosis, in which monoamine oxidase B (MAO-B) activity is increased. In vitro autoradiography of the corresponding lesion demonstrated specific binding of 18F-THK5351, which was blocked by an MAO-B–selective ligand. Thus, 18F-THK5351 PET may reflect glioblastomas and associated gliosis by binding to MAO-B.

Capillary endothelial cells in the brain express P-glycoprotein (P-gp), which works as a functional blood-brain barrier (BBB). P-gp pumps out multiple types of molecules from the brain parenchyma into the blood. Therefore, altered P-gp function at the BBB will change the concentrations of therapeutic drugs in the central nervous system (CNS) and hence impact the toxicity and efficacy of CNS drugs. Positron emission tomography (PET) is the only way to non-invasively measure P-gp function in the living human brain. PET imaging of P-gp function was first demonstrated in 1998 with the substrate tracer racemic [11C]verapamil. Since then, several drug interaction studies and proof-of-concept studies regarding drug resistance have been performed with P-gp PET imaging. Although preclinical findings have been very positive regarding the possibilities and importance of P-gp PET imaging, very few studies have shown the clinical relevance of P-gp PET imaging in different disorders of the brain. This review summarizes the pharmacological studies with PET using substrate tracers and emphasizes the importance of PET imaging to understand the mechanism of action of CNS drugs.

We prospectively compared the diagnostic value of PETcomputed tomography (CT) findings using the tracers 4′-methyl-11C-thiothymidine (11C-4DST) and 2-deoxy-2-18F-fluoro-D-glucose (18F-FDG) in patients with head and neck squamous cell carcinoma (HNSCC).

Objective: Histamine H1receptor (H1R) antagonists often have sedative side effects, which are caused by the blockade of the neural transmission of the histaminergic neurons. We examined the brain H1R occupancy (H1RO) and the subjective sleepiness of levocetirizine, a new second-generation antihistamine, comparing fexofenadine, another non-sedating antihistamine, as a negative active control.Methods: Eight healthy volunteers underwent positron emission tomography (PET) imaging with [11C]doxepin, a PET tracer that specifically binds to H1Rs, after a single oral administration of levocetirizine (5 mg), fexofenadine (60 mg) or placebo in a double-blind crossover study. Binding potential ratios and H1ROs in the cerebral cortices regions were calculated using placebo. Subjective sleepiness was assessed with the Line Analogue Rating Scale and the Stanford Sleepiness Scale.Results: There was no significant difference between the mean brain H1RO after levocetirizine administration (8.1%; 95% CI: −9.8 to 26.0%) and fexofenadine administration (−8.0%; 95% CI: −26.7 to 10.6%). Similarly, subjective sleepiness was not significantly different between the two antihistamines and placebo. Neither subjective sleepiness nor plasma concentrations was significantly correlated with the brain H1RO of the two antihistamines.Conclusion:At therapeutic dose, levocetirizine does not bind significantly to the brain H1Rs and does not induce significant sedation.

We examined differences in brain activity in response to two types of mechanical stimulation, which have been reported previously as being perceptually indistinguishable but having different impacts on autonomic reflexes. As an indicator of brain activity, glucose metabolism was evaluated by PET with 2-18Ffluoro-2-deoxy-D-glucose (18F-FDG). Twelve healthy, young adult men participated in the study. Two types of cutaneous stimulation tools, soft elastomer discs with microcones (microcone disc) or flat surfaces (flat disc), were used in a crossover, randomized double-blind manner. Each type of cutaneous stimulation tool was applied on the cheeks and 18F-FDG-PET scans were obtained. Greater 18F-FDG uptake was observed in the right anterior cingulate cortex during microcone disc stimulation compared with flat disc stimulation. However, 18F-FDG uptake during application of these two different stimuli was not different in the primary and secondary somatosensory cortices or insula. Stimulation using microcone discs and flat discs was noted by one and three participants, respectively, and there was no difference in the presence of perception between the stimulation tools. The results indicate that the right anterior cingulate cortex differentially responds to different types of cutaneous stimulation that are perceptually indistinguishable.

Accumulating evidence suggests that σ1 receptors play a role in the mechanisms of action of some therapeutic drugs, such as the selective serotonin reuptake inhibitors (SSRIs), donepezil, and ifenprodil. Among the SSRIs, fluvoxamine, a potent σ1 receptor agonist, has the highest affinity for σ1 receptors, while donepezil and ifenprodil also show high affinity for σ1 receptors. These drugs affect neuronal plasticity indicated by potentiation of nerve-growth factor (NGF)-induced neurite outgrowth in PC12 cells. Furthermore, phencyclidine (PCP)-induced cognitive impairment, associated with animal models of schizophrenia, is significantly improved by sub-chronic administration of fluvoxamine and donepezil. These pharmacological actions are antagonised by treatment with the selective σ1 receptor antagonist NE-100. Positron emission tomography (PET) with the σ1 specific ligand carbon-11-labelled 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine ([11C]SA4503) indicated that fluvoxamine and donepezil can bind to σ1 receptors in the healthy human brain in a dose-dependent manner. These findings suggest that σ1 receptors may be involved in the mechanisms of action of some therapeutic drugs.

The α7 nicotinic acetylcholine receptors (nAChRs), ligand-gated Ca2+ channels composed of homopentamers of α7 subunits, represent the most abundant with α4β2 nAChRs in the brain. Several lines of evidence suggest that α7 nAChRs play a role in the physiology of neuropsychiatric diseases such as schizophrenia, Alzheimer's disease, anxiety, depression, and drug addiction; hence, α7 nAChRs seem to be attractive therapeutic targets for these diseases. Several researchers have attempted to develop radioligands that can be used to selectively and quantitatively examine the distribution of α7 nAChRs in the human brain with positron emission tomography (PET) or single photon emission tomography (SPECT). Although efforts are underway, very low density of α7 nAChR and scarcity of very high affinity ligands hamper the development of α7 subtype-selective radioligands for in vivo imaging. In this article, we review the recent topics on the development of PET/SPECT ligands for in vivo imaging of α7 nAChRs in the brain.

The 7 nicotinic acetylcholine receptors (nAChRs), ligand-gated Ca2 channels composed of homopentamers of 7 subunits, represent the most abundant with 42 nAChRs in the brain. Several lines of evidence suggest that 7 nAChRs play a role in the physiology of neuropsychiatric diseases such as schizophrenia, Alzheimers disease, anxiety, depression, and drug addiction; hence, 7 nAChRs seem to be attractive therapeutic targets for these diseases. Several researchers have attempted to develop radioligands that can be used to selectively and quantitatively examine the distribution of 7 nAChRs in the human brain with positron emission tomography (PET) or single photon emission tomography (SPECT). Although efforts are underway, very low density of 7 nAChR and scarcity of very high affinity ligands hamper the development of 7 subtype-selective radioligands for in vivo imaging. In this article, we review the recent topics on the development of PET/SPECT ligands for in vivo imaging of 7 nAChRs in the brain.

Accumulating evidence suggests that α7 nicotinic receptors (α7 nAChRs), a subtype of nAChRs, play a role in the pathophysiology of neuropsychiatric diseases, including schizophrenia and Alzheimer’s disease (AD). A number of psychopharmacological and genetic studies shown that α7 nAChRs play an important role in the deficits of P50 auditory evoked potential in patients with schizophrenia, and that (α nAChR agonists would be potential therapeutic drugs for cognitive impairments associated with P50 deficits in schizophrenia. Furthermore, some studies have demonstrated that α7 nAChRs might play a key role in the amyloid-β (Aβ)-mediated pathology of AD, and that α7 nAChR agonists would be potential therapeutic drugs for Aβ deposition in the brains of patients with AD. Interestingly, the altered expression of α7 nAChRs in the postmortem brain tissues from patients with schizophrenia and AD has been reported. Based on all these findings, selective α7 nAChR agonists can be considered potential therapeutic drugs for cognitive impairments in both schizophrenia and AD. In this article, we review the recent research into the role of α7 nAChRs in the pathophysiology of these diseases and into the potential use of novel α7 nAChR agonists as therapeutic drugs.

Sigma1 receptors were imaged in living human brain by positron emission tomography (PET) using [11C] SA4503. A dynamic 90-min scan and kinetic analysis enabled quantification of receptor density in the brain. The sigma1 receptors were distributed throughout the brain in normal subjects, but decreased in the frontal, temporal, and occipital lobes, cerebellum and thalamus in patients with early Alzheimers disease and in the putamen in patients with Parkinsons disease. In addition, rates of receptor occupancy by the neuroleptic haloperidol and the selective serotonin reuptake inhibitor fluvoxamine were evaluated by [11C]SA4503-PET and found to be high. [11C]SA4503-PET is useful for studying the pathophysiology of neurological and psychiatric disorders such as schizophrenia and for evaluation of the pharmacodynamics of psychiatric drugs.

Cerebral acetylcholinesterase (AChE) imaging is not only useful for diagnosis of dementia disorders but also for therapeutic monitoring of the effects of cholinesterase (ChE) inhibitors and for decision of the appropriate clinical dosage of newly developed ChE inhibitors. Several ChE inhibitors or the derivatives such as 1,2,3,4-tetrahydro-9-methylaminoacridine (MTHA), donepezil, physostigmine, CP126,998 and 2-fluoro-CP118,954 have been labeled with positron emitters for mapping cerebral AChE by positron emission tomography (PET). When [11C]MTHA or [11C]donepezil was injected in animals, the uptake poorly reflect the regional distribution of AChE in the brain because of high non-specific binding and/or less specific to AChE in vivo in the brain tissue. [11C]physostigmine, [11C]CP126,998 and 2-[18F]fluoro-CP118,954 were distributed corresponding well to the regional AChE activity in animals, and also former two probes were successfully applied to clinical PET trial. The other approach is measuring cerebral AChE activity with radiolabeled acetylcholine analogue substrates. We have developed the principle for measuring cerebral enzyme activity by PET and radiolabeled N-methylpiperidinyl esters for quantitative measurement of cerebral AChE activity. N-[11C]methylipiperidin-4-yl acetate (MP4A) and N-[11C]methylpiperidin-4-yl propionate (MP4P) have been used for clinical studies of other demented disorders including Alzheimer's disease (AD), and the probes have demonstrated not only the reduction of AChE activity in the cerebral cortex of patients with AD but also the inhibitory effects of donepezil and rivastigmine on AChE activity in the brain of AD patients. Following this succession, widely available [18F]-labeled derivatives of MP4A and MP4P have been developed based on the structure-activity relationships between AChE and piperidinol esters.