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Aims Abnormality of cognitive function in schizophrenia has been suggested to be related to dopamine D1 receptor. However, the results of previous positron emission tomography (PET) studies of dopamine D1 receptor in schizophrenia were not consistent. Main methods In this study, six patients with schizophrenia in severe residual phase with chronic antipsychotic treatment and twelve healthy age-matched controls participated. Two different radioligands, [11C]NNC112 and [11C]SCH23390, for dopamine D1 receptor were used on the same subjects. Binding of the ligands was measured by PET, and statistical analysis was performed using one-way analysis of covariate (ANCOVA) with age as covariate. Key findings Good correlations between binding potential values (BPND) and age were observed in all regions of interest (ROIs) with both ligands. ANCOVA with age as covariate of BPND values of all ROIs revealed that the patient group showed significantly lower BPND value compared with the control group in both ligands. Significance In patients with chronic schizophrenia in severe residual phase with chronic antipsychotic treatment, the binding potential values of both ligands were significantly lower in the striatum and cortical regions than those of healthy controls.

The serotonin transporter (5-HTT) and other markers of the serotonergic system have been of interest in the pathophysiology of obsessive-compulsive disorder (OCD). Previous studies using single photon emission computed tomography (SPECT) with [(123)I]beta-CIT or positron emission tomography (PET) with [(11)C]McN5652 have not shown consistent findings about 5-HTT in OCD patients. The aim of the present study was to investigate 5-HTT binding using [(11)C]DASB, which has higher selectivity or specific binding-to-nonspecific binding ratios for 5-HTT compared to the aforementioned radioligands. Four drug-naive and 6 drug-free patients with OCD who were free of comorbid depression and 18 gender and age-matched healthy subjects underwent PET scans with [(11)C]DASB. The severity of OCD was assessed by Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) (mean+/-SD: 22+/-7.6, range: 7-32). The binding potential (BP(ND)) of [(11)C]DASB was calculated using a two-parameter multilinear reference tissue model (MRTM2). The parametric images of BP(ND) were analyzed using a statistical parametric mapping system. Significant reductions of BP(ND) were observed in the right posterior and left anterior insular cortices in patients with OCD compared to controls. Region-of-interest analysis has also confirmed significant reduction of BP(ND) in the insular cortex. Although significantly reduced BP(ND) in the orbitofrontal cortex was also observed in patients with OCD compared to controls, this finding should be considered with caution because of the very low 5-HTT binding in the region. On the other hand, no significant correlation was observed between the Y-BOCS score and BP(ND). The change in [(11)C]DASB binding in the insular cortex suggests that dysfunction of the serotonergic system in the limbic area might be involved in the pathophysiology of OCD.

セロトニントランスポーターは多くの抗うつ薬の主要な結合部位のひとつであり，うつ病の発現に重要な役割を果たしていることが想定されている．PET（positron emission tomography）では，セロトニントランスポーターに特異結合する放射性リガンドを用いて，ヒト脳内のセロトニントランスポーターをin vivoで定量することが可能である．実際に，PET研究で，視床のセロトニントランスポーターがうつ病患者群において，増加していることが報告されており，セロトニントランスポーターがうつ病の病態に大きな役割を果たしていると推察できる．また，健常者において，うつ病の発症脆弱性が，視床におけるセロトニントランスポーターの発現と関連している可能性もPET研究から示唆されている．一方，セロトニン神経系の起始核がある中脳での有意な変化は，PET研究では報告されておらず，今後の知見の集積がまたれる．抗うつ薬のPETによる評価としては，セロトニントランスポーターに対して特異的に結合する放射性リガンドと抗うつ薬が競合阻害することから，占有率を算出して評価する方法が一般的である．PETを用いて，抗うつ薬による脳内セロトニントランスポーターの占有率およびその経時変化を測定することで，血中の薬剤濃度や半減期に比して，より適切な臨床用量や投与方法が設定可能である．実際に，既存の薬剤の再評価に加え，日本国内でも，新規抗うつ薬の治験にPETが使用されている．今後，新規の抗うつ薬の開発にPETが重要な役割を果たすことが，期待されている．

Background An abnormality in regional cerebral blood flow (rCBF) in anorexia nervosa (AN) patients has been reported. There are very few studies that have investigated the rCBF changes in the recovery process of AN. Methods For eight female AN patients, we performed 123 I-IMP single photon emission computed tomography (SPECT) and four psychological assessments (Eating Disorder Inventory (EDI), Eating Attitude Test (EAT), Self-Rating Depression Scale (SDS) and State-Trait Anxiety Inventory (STAI)) both before and after inpatient-behavioral therapy. SPECT images were analyzed using statistical parametric mapping software. We also performed correlational analysis between rCBF and clinical variables. Results Following treatment, the patients showed significant body weight recovery. They showed significant improvement in EAT, SDS, STAI and a subscale of EDI – interoceptive awareness (IA) – but not in total EDI or other EDI subscales. Significant rCBF increases were observed in the precuneus, posterior cingulate cortex (PCC), right dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC) and medial prefrontal cortex (MPFC) by the treatment. Significant correlation was observed between rCBF of right DLPFC and IA score before treatment. Conclusions Changes of rCBF in right DLPFC, ACC, MPFC, PCC and precuneus were related to the AN recovery process and might be associated with improvement of IA following treatment.

N-methyl-D-aspartate (NMDA) receptors are of major interest in brain functions and neuropsychiatric disorders. However, at present there are few suitable radioligands for in vivo imaging of NMDA receptors. 7-choloro-4-hydroxy-3-[3-(4-methoxybenzyl) phenyl]-2(1H)-quinolone (L-703,717) is one of the potent ligands for the glycine-binding site of NMDA receptors. 4-Acetoxy derivative of L-703,717 (AcL703) is a candidate, as a positron emission tomography (PET) ligand for NMDA receptors, because of its better permeability at the blood-brain barrier compared with L-703,717. After intravenous injection of 624-851 MBq of [11C]AcL703, dynamic PET scan was performed on six healthy males for 90 min. Regions-of-interest were located on the cerebral cortices, cerebellar cortex, and cerebral white matter. The binding potential (BP) was calculated from the ratio of the area under the curve (AUC) of radioactivities from 40 to 90 min in the target region to that in white matter. Regional radioactivities reached close to equilibrium in all regions after about 40 min postinjection. Regional brain uptake of [11C]AcL703 at 40 min after injection was 0.00028-0.00065% of the injected dose/milliliter. Radioactivity concentration of [11C]AcL703 was highest in the cerebellar cortex and lowest in white matter. AUC in the cerebellar cortex was higher than those of cerebral cortices, thalamus, striatum, and white matter. BP in the cerebellar cortex was twofold higher than in the cerebral cortices (cerebellar cortex: BP=2.20+/-0.72; cerebral cortices: BP=1.05+/-0.45). Despite the low brain uptake of [11C]AcL703, regional distributions were in good agreement with our previous studies of rodents. This indicates the possibility of in vivo evaluation of NMDA receptors using PET with [11C]AcL703 in living human brain.

When humans manipulate a control device under operational rules, with the goal of indirectly controlling a remote tool to achieve a desired outcome, they may rely on the power of internal representation to organize individual moves of the controller and tool into a set of sequences by mapping the motor space among hand, controller and tool. We recently used functional brain imaging (PET) to investigate activations in monkey brain associated with joystickcontrolled remote operation of a shovel to obtain food. Activated areas included the prefrontal cortex, posterior parietal cortex and cerebellum, regardless of the rules relating movements of the joystick to those of the shovel (Obayashi et al., 2004). If those areas are engaged in the mental manipulation of internal representation, then we should expect brain activity in the same regions during any similar remote operation, even with different controllers and/or operational rules. To address the above hypothesis in the current study, we used PET to measure regional cerebral blood flow (rCBF) of two monkeys during a task in which they were required to control a shovel remotely (to fetch a food pellet) by manipulating dual dials. Compared to unplanned movement of the dials, the active dual-dial operation was associated with robust activation of the prefrontal cortex, higher-order motor cortex, posterior parietal cortex and cerebellum, quite similar to that observed during remote operation with a joystick. The present study suggests that monkeys might be able to organize abstract sequential operations according to learned rules, and perhaps indeed to have insight into the nature of the causal relationships, implying the existence of a relatively sophisticated system of internal representation in the absence of language. The fact that the present results are consistent with our previous PET studies strengthens the view that the underlying mechanism for implicit manipulation of internal representations may involve a cerebro-cerebellar neural circuit including the frontal and parietal cortex.

N-(5-Fluoro-2-phenoxyphenyl)-N-(2-(18)F-fluoroethyl-5-methoxybenzyl)acetamide ((18)F-FEDAA1106) is a potential PET ligand with highly selective and specific binding to peripheral benzodiazepine receptor (PBR). It has been reported that the regional density of PBR in the brain is increased in several neurodegenerative and psychiatric disorders. Thus, a reliable tracer method for evaluating PBR would be of use clinically and for research. To our knowledge, this is the first study to investigate the (18)F-FEDAA1106 binding to PBR in living human brain by PET. We also aimed to evaluate various analytic methods to quantify the density of PBR.PET studies with (18)F-FEDAA1106 were performed on 7 healthy men. Volumes of interest (VOIs) were drawn on PET images. In each VOI, binding potential (BP) was calculated by nonlinear least-squares (NLS) fitting based on the 2-tissue compartment model, and the distribution volume (DV) was also estimated by NLS, Logan plot, and multilinear analysis (MA) methods. To estimate errors in calculation of BP and DV, simulation studies were also performed.The DVs estimated with each of the methods were significantly correlated. There was also significant correlation between BP with NLS and DV with NLS, Logan plot, or MA. But the interindividual differences in the distribution volume of the free and nonspecific binding compartment (K(1)/k(2)) were relatively large. In a simulation study, variation of the DV estimated by Logan plot was relatively small, but it was underestimated as the noise increased. By MA, the bias of DV was smaller, but the variation of DV was larger than by Logan plot. Within a 3% noise level, there was almost no difference between Logan plot and MA in both bias and variation. DVs estimated by both Logan plot and MA were underestimated by 10%-20%. Although the variation of DV was larger by NLS than by Logan plot, it was small enough in the noise level of VOI analysis, and the bias of DV was 0%-2%.The simulation studies indicated that NLS is a suitable method for the estimation of (18)F-FEDAA1106 binding to PBRs.

Positron Emission Tomography (PET) allows in vivo visualization of the expression and function of protein using a radioligand. Quantitative analysis of serotonin transporter, receptors, and the function of P-Glycoprotein has been performed in living human brains. Furthermore, the relationship between the phenotype of those proteins and their genetic polymorphism has also been investigated. Regarding the effect of antipsychotics on dopamine D2 receptor, occupancy and its time-course have been measured in a living body using PET. This approach can provide in vivo pharmacological evidences of antipsychotics and establish a rational therapeutic strategy. PET is a powerful tool not only in the field of brain research but also drug discovery and individual medicine.