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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.

Recently, we developed [methyl-11 C]49-thiothymidine ( 11 C-4DST) as an in vivo cell proliferation marker. The present study was performed to determine the safety, distribution, radiation dosimetry, and initial brain tumor imaging of 11 C-4DST in humans. Methods: Multiorgan biodistribution and radiation dosimetry of 11 C-4DST were assessed in 3 healthy humans, who underwent 2-h whole-body PET scanning. Radiation dosimetry was estimated from the residence times of source organs using the OLINDA program. Six brain tumor patients underwent dynamic 11 C-4DST scans with arterial blood sampling. These patients were also evaluated with 11 C-methionine PET on the same day (n 5 4) as, or 3 wk before (n 5 2), 11 C-4DST PET studies. Metabolites in plasma and urine samples were analyzed by high-performance liquid chromatography. Breakdown of the blood-brain barrier in tumor tissue was confirmed by gadolinium-enhanced T1-weighted MRI. Results: There were no serious adverse events in any subjects at any time during the study period. 11 C-4DST PET demonstrated selective uptake in the bone marrow, which has a high rate of proliferation. In addition, high-level uptake was also seen in the liver. The highest absorbed organ dose was in the urinary bladder wall (17.6 mGy/MBq). The estimated effective dose for 11 C-4DST was 4.2 mSv/MBq. 11 C-4DST showed little uptake in normal brain tissues, resulting in low background activity for imaging of brain tumors. In contrast, 11 C-4DST PET demonstrated rapid uptake in aggressive tumor masses, whereas no signal of 11 C-4DST was seen in clinically stable disease in which 11 C-methionine uptake was high. The distribution pattern of 11 C-methionine in tumor regions was not always identical to that of 11 C-4DST. Analysis of plasma samples by high-performance liquid chromatography indicated that more than 60% of the radioactivity was present as unchanged 11 C-4DST at 20 min. Conclusion: The initial findings of the present study in a small group of patients indicated that 11 C-4DST PET is feasible for imaging of brain tumors. Dosimetry and pharmacologic safety were acceptable at the dose required for adequate PET images.

These results demonstrate that [(11)C]CHIBA-1001 is a suitable radioligand to use in clinical trials for imaging alpha7 nAChRs in the human brain, providing acceptable dosimetry and pharmacological safety at the dose required for adequate PET imaging.

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The acetylcholinesterase (AChE) inhibitor donepezil is also a sigma1 receptor agonist. We examined whether donepezil binds to sigma1 receptors in the living human brain after a single oral administration. Dynamic positron emission tomography (PET) data acquisition using the selective sigma1 receptor ligand [11C]SA4503 was performed to evaluate quantitatively the binding of [11C]SA4503 to sigma1 receptors in eight healthy male volunteers. Each subject had a PET scan before and after receiving a single dose of donepezil (5 or 10 mg). The binding potential of [11C]SA4503 was calculated. Doses of 5 mg and 10 mg donepezil bound to sigma1 receptors in the human brain with occupancies of approximately 60% and approximately 75%, respectively, in a dose-dependent manner. This study demonstrated that donepezil binds to sigma1 receptors in the living human brain at therapeutic doses. Therefore, sigma1 receptors may be implicated in the pharmacological mechanism of donepezil in the human brain.

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