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The kinetics of 18F-fluorodeoxyglucose (18F-FDG) in the monkey brain were monitored, and comparisons were made between the conscious state and when under ketamine and pentobarbital anesthesia. Rhesus monkeys were intravenously injected with 18F-FDG and followed by 60 min of PET scanning. In the conscious state, the 18F-FDG concentration reached a plateau 5 min after intravenous injection. Under ketamine anesthesia, the 18F-FDG concentration gradually increased with time in all monitored regions. At 60 min after injection, the concentration in the striatum was about 3.2 times greater than that in the conscious state, and about 4.5 times greater in the cerebral cortex. Under pentobarbital anesthesia, the 18F-FDG concentration in the occipital cortex was slightly lower. These findings demonstrate that 18F-FDG concentration in the monkey brain is significantly affected by anesthesia. The results also imply the existence of a short-term regulation mechanism for hexokinase activity in intact monkey brain.

In this study, we report the synthesis and reactivity of [ 18 F]fluoromethyl iodide ([ 18 F]FCH 2 I) with various nucleophilic substrates and the stabilities of [ 18 F]fluoromethylated compounds. [ 18 F]FCH 2 I was prepared by reacting diiodomethane (CH 2 I 2 ) with [ 18 F]KF, and purified by distillation in radiochemical yields of 14–31% ( n = 25). [ 18 F]FCH 2 I was stable in organic solvents commonly used for labeling and aqueous solution with pH 1–7, but was unstable in basic solutions. [ 18 F]FCH 2 I displayed a high reactivity with various nucleophilic substrates such as phenol, thiophenol, amide and amine. The [ 18 F]fluoromethylated compounds synthesized by the reactions of phenol, thiophenol and tertiary amine with [ 18 F]FCH 2 I were stable for purification, formulation and storage. In contrast, the [ 18 F]fluoromethylated compounds synthesized by the reactions of primary or secondary amines, and amide with [ 18 F]FCH 2 I were too unstable to be detected or purified from the reaction mixtures. Defluorination of these [ 18 F]fluoromethyl compounds was a main decomposition route.

The reduction of acetylcholinesterase (AChE) activity in the brain has been measured in dementia disorders such as Alzheimer's disease and dementia with Lewy bodies using (11)C-labeled acetylcholine analogues, N-[(11)C]methylpiperidin-4-yl acetate and propionate, and positron emission tomography (PET). Our aim was to develop an (18)F-labeled acetylcholine analogue useful for brain AChE mapping with PET, since (18)F, with a longer half-life, has advantages over (11)C. In a preliminary study, a series of N-[(14)C]ethylpiperidin-3-yl or -4-ylmethanol esters (acetyl and propionyl esters) were newly designed and evaluated in vitro regarding the reactivity with and specificity to AChE using purified human enzymes, leading to a novel (18)F-labeled acetylcholine analogue, N-[(18)F]fluoroethylpiperidin-4-ylmethyl acetate. In rat experiments, the (18)F-labeled candidate showed desirable properties for PET AChE measurement: high brain uptake of the authentic ester, high AChE specificity, a moderate hydrolysis rate, and low membrane permeability (metabolic trapping) of the metabolite.

To develop a positron emission tomography (PET) ligand for imaging the 'peripheral benzodiazepine receptor' (PBR) in brain and elucidating the relationship between PBR and brain diseases, four analogues (4-7) of N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (2) were synthesized and evaluated as ligands for PBR. Of these compounds, fluoromethyl (4) and fluoroethyl (5) analogues had similar or higher affinities for PBR than the parent compound 2 (K(i) = 0.16 nM for PBR in rat brain sections). Iodomethyl analogue 6 displayed a moderate affinity, whereas tosyloxyethyl analogue 7 had weak affinity. Radiolabeling was performed for the fluoroalkyl analogues 4 and 5 using fluorine-18 ((18)F, beta(+); 96.7%, T(1/2) = 109.8 min). Ligands [(18)F]4 and [(18)F]5 were respectively synthesized by the alkylation of desmethyl precursor 3 with [(18)F]fluoromethyl iodide ([(18)F]8) and 2-[(18)F]fluoroethyl bromide ([(18)F]9). The distribution patterns of [(18)F]4 and [(18)F]5 in mice were consistent with the known distribution of PBR. However, compared with [(18)F]5, [(18)F]4 displayed a high uptake in the bone of mice. The PET image of [(18)F]4 for monkey brain also showed significant radioactivity in the bone, suggesting that this ligand was unstable for in vivo defluorination and was not a useful PET ligand. Ligand [(18)F]5 displayed a high uptake in monkey brain especially in the occipital cortex, a region with richer PBR than the other regions in the brain. The radioactivity level of [(18)F]5 in monkey brain was 1.5 times higher than that of [(11)C]2, and 6 times higher than that of (R)-(1-(2-chlorophenyl)-N-[(11)C]methyl,N-(1-methylpropyl)isoquinoline ([(11)C]1). Moreover, the in vivo binding of [(18)F]5 was significantly inhibited by PBR-selective 2 or 1, indicating that the binding of [(18)F]5 in the monkey brain was mainly due to PBR. Metabolite analysis revealed that [(18)F]4 was rapidly metabolized by defluorination to [(18)F]F(-) in the plasma and brain of mice, whereas [(18)F]5 was metabolized by debenzylation to a polar product [(18)F]13 only in the plasma. No radioactive metabolite of [(18)F]5 was detected in the mouse brain. The biological data indicate that [(18)F]5 is a useful PET ligand for PBR and is currently used for imaging PBR in human brain.

Purpose: The development of the novel carbon ion radiotherapy (CIRT) in the treatment of refractory cancers has resulted in the need for a way to accurately evaluate patient prognosis. We evaluated whether l-[methyl-11C]-methionine (MET) uptake and its change after CIRT were the early survival predictors in patients with unresectable bone and soft tissue sarcomas. Experimental Design: MET positron emission tomography was prospectively performed in 62 patients with unresectable bone and soft tissue sarcomas before and within 1 month after CIRT. Tumor MET uptake was measured with the semiquantitative tumor:nontumor ratio (T/N ratio). The MET uptake in the tumor and relevant clinical parameters were entered into univariate and multivariate survival analysis. Results: The overall median survival time was 20 months. Patients with a baseline T/N ratio of ≤6 had a significant better survival than patients with a baseline T/N ratio >6 (2-year survival rate: 69.4% versus 32.3%; P = 0.01). Patients with a post-CIRT ratio of ≤4.4 had a better survival than that with a post-CIRT ratio >4.4 (2-year survival rate: 63.7% versus 41.3%; P = 0.01). A significant higher survival rate was observed in patients with post-therapeutic MET uptake change of >30% than patients in lower change group (2-year survival rate: 74.6% versus 41.6%; P = 0.049). The multivariate analysis showed that both baseline and post-CIRT T/N ratio were statistically significant independent predictors of patient survival. Tumors with larger T/N ratio had a significantly poorer prognosis. Conclusions: MET uptake as measured by either baseline or post-CIRT T/N ratio was an independent predictor of survival in patients with bone and soft tissue sarcomas treated by carbon ion radiotherapy, whereas post-therapeutic MET uptake change might have potential value for the same purpose.

In Alzheimer's disease, cerebral cortical butyrylcholinesterase (BChE) activity is reported to be elevated. Our aim was to develop a novel (18)F-labeled tracer for quantifying cerebral BChE activity by positron emission tomography. With in vitro screening of N-[(14)C]ethylpiperidin-3- and 4-ylmethyl esters, N-[(14)C]ethylpiperidin-4-ylmethyl butyrate was selected as a lead for (18)F-labeling, affording N-[(18)F]fluoroethylpiperidin-4-ylmethyl butyrate. The (18)F-labeled butyrate showed the required properties for in vivo BChE measurement, that is, the lipophilic nature of the authentic ester, high specificity to BChE, a moderate hydrolysis rate, and the hydrophilic nature of the metabolite.

We performed in vitro and in vivo assays of the metabolism of [ 11 C]Ro15-4513 over time in the plasma of mice, rats, monkeys and humans, using a radio-HPLC equipped with a sensitive positron detector, in order to compare the metabolic rates of the radiopharmaceutical agent among the different animal species and to establish a highly sensitive analytical method for the radiotracer agent. We also examined the metabolism of [ 11 C]Ro15-4513 in the brain tissue of mice and rats. The analytical method used in this study permitted detection of even extremely low levels of radioactivity (approximately 5,000 dpm). In vitro experiments revealed that [ 11 C]Ro15-4513 in the blood was metabolized to hydrolysate [ 11 C]A. The species were classified in descending order of the metabolic rate of the radiotracer in vitro as follows; mice, rats, and monkeys/humans. In the in vitro experiment, the percentage of the unchanged drug in the plasma at 60 minutes postdose was 9% in mice, 70% in rats, 97% in monkeys, and 98% in humans. In vivo metabolite analysis in the blood showed the presence of two radioactive metabolites, consisting of one hydrolysate [ 11 C]A and another unidentified substance. The species were classified in descending order of the metabolic rate of the radiotracer in vivo as follows; mice, rats/humans, and monkeys. The percentage of the unchanged drug in the plasma was 6% in mice, 21% in rats, 26% in humans, and 40% in monkeys. Furthermore, the in vitro and in vivo experiments conducted to analyze the metabolism of [ 11 C]Ro15-4513 in the brain tissue of mice and rats revealed that the radiotracer was metabolized to some extent in the brain tissue of these animals. In the in vivo experiment, the percentage of the unchanged drug at 60 min postdose was 86% in the brain tissue of mice and 88% in the brain tissue of rats, while in the in vitro experiment, the corresponding percentage was 93% in mice, and 91% in rats.

A positron-emitter (carbon-11) labeled antagonist for the glycine-binding site of NMDA receptors, [(11)C]L-703,717, has a unique in vivo binding characteristic, in which it preferentially binds to cerebellar-specific NMDA receptors consisting of a GluRepsilon3 subunit and eventually accumulates in rodent cerebellum under in vivo conditions, but not under in vitro conditions. In order to understand the in vivo-specific site and subunit localization of this radioligand, we examined the effect of the endogenous glycine site agonists, glycine and D-serine, on in vivo [(11)C]L-703,717 binding. An increase in extracellular glycine concentration by treatment with a glycine transporter 1 (GlyT1)-selective inhibitor, NFPS ethyl ester, significantly decreased the cerebellar localization of [(11)C]L-703,717 in rats. D-serine is known to be concentrated in mammalian forebrain regions. The lack of D-serine detection in the cerebellum may be due to the fact that it has the highest enzymatic activity of D-amino acid oxidase (DAO). It was found that the cerebellar localization of [(11)C]L-703,717 is greatly diminished in mutant mice lacking DAO, in which D-serine content in the cerebellum is drastically increased from a nondetectable level in normal mice. These studies indicate that [(11)C]L-703,717 is susceptible to inhibition by glycine site agonists in its in vivo binding, and suggest that regional differences in inhibitions by endogenous agonists may be a crucial factor in the site- and subunit-specific binding of this glycine-site antagonist.

DAA1106 (N-(2,5-Dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide), is a potent and selective ligand for peripheral benzodiazepine receptors (PBR) in mitochondrial fractions of rat (K(i)=0.043 nM) and monkey (K(i)=0.188 nM) brains. This compound was labeled by [(11)C]methylation of a corresponding desmethyl precursor (DAA1123) with [(11)C]CH(3)I in the presence of NaH, with a 72+/-16% (corrected for decay) incorporation yield of radioactivity. After HPLC purification, [(11)C]DAA1106 was obtained with > or =98% radiochemical purity and specific activity of 90-156 GBq/micromol at the end of synthesis. After iv injection of [(11)C]DAA1106 into mice, high accumulations of radioactivity were found in the olfactory bulb and cerebellum, the high PBR density regions in the brain. Coinjection of [(11)C]DAA1106 with unlabeled DAA1106 and PBR-selective PK11195 displayed a significant reduction of radioactivity, suggesting a high specific binding of [(11)C]DAA1106 to PBR. Although this tracer was rapidly metabolized in the plasma, only [(11)C]DAA1106 was detected in the brain tissues, suggesting the specific binding in the brain due to the tracer itself. These findings revealed that [(11)C]DAA1106 is a potential and selective positron emitting radioligand for PBR.

An aqueous solution of [(11)C]Ro 15-4513 underwent decomposition to give a few radioactive degradation products. The major degradation product corresponded to that of authentic Ro 15-4513 with (60)Co radiolysis, which showed a molecular weight of 301 (M+H). The structure of this degradation product was estimated to have an amine group instead of an azido group on Ro 15-4513. Radiolysis of Ro 15-4513 was not suppressed by the addition of selective hydroxyl radical scavenger (MeOH, HCOO(-)), in contrast, it was suppressed effectively in the presence of a selective hydrated electron scavenger (NaNO(3)), suggesting that hydrated electrons would play an important role in the radiolysis of [(11)C]Ro 15-4513.

N-[(18)F]Fluoroethyl-4-piperidyl acetate ([(18)F]FEtP4A) was synthesized and evaluated as a PET tracer for imaging brain acetylcholinesterase (AchE) in vivo. [(18)F]FEtP4A was previously prepared by reacting 4-piperidyl acetate (P4A) with 2-[(18)F]fluoroethyl bromide ([(18)F]FEtBr) at 130 degrees C for 30 min in 37% radiochemical yield using an automated synthetic system. In this work, [(18)F]FEtP4A was synthesized by reacting P4A with 2-[(18)F]fluoroethyl iodide ([(18)F]FEtI) or 2-[(18)F]fluoroethyl triflate ([(18)F]FEtOTf in improved radiochemical yields, compared with [(18)F]FEtBr under the corresponding condition. Ex vivo autoradiogram of rat brain and PET summation image of monkey brain after iv injection of [(18)F]FEtP4A displayed a high radioactivity in the striatum, a region with the highest AchE activity in the brain. Moreover, the distribution pattern of (18)F radioactivity was consistent with that of AchE in the brain: striatumfrontal cortexcerebellum. In the rat and monkey plasma, two radioactive metabolites were detected. However, their presence might not preclude the imaging studies for AchE in the brain, because they were too hydrophilic to pass the blood-brain barrier and to enter the brain. In the rat brain, only [(18)F]fluoroethyl-4-piperidinol ([(18)F]FEtP4OH) was detected at 30 min postinjection. The hydrolytic [(18)F]FEtP4OH displayed a slow washout and a long retention in the monkey brain until the PET experiment (120 min). Although [(18)F]FEtP4A is a potential PET tracer for imaging AchE in vivo, its lower hydrolytic rate and lower specificity for AchE than those of [(11)C]MP4A may limit its usefulness for the quantitative measurement for AchE in the primate brain.

Although [(11)C]Ro15-4513 and [(11)C]flumazenil both bind to the central benzodiazepine (BZ) receptors, the distributions of the two ligands are not identical in vivo. Moreover, the in vivo pharmacological properties of [(11)C]Ro15-4513 have not been thoroughly examined. In the present study, we examined the pharmacological profile of [(11)C]Ro15-4513 binding in the monkey brain using positron emission tomography (PET). [(11)C]Ro15-4513 showed relatively high accumulation in the anterior cingulate cortex, hippocampus, and insular cortex, with the lowest uptake being observed in the pons. Accumulation in the cerebral cortex was significantly diminished by the BZ antagonist flumazenil (0.1 mg/kg, i.v.), but not that in the pons. Using the pons as a reference region, the specific binding of [(11)C]Ro15-4513 in most of the cerebral cortex including the limbic regions clearly revealed two different affinity sites. On the other hand, specific binding in the occipital cortex and cerebellum showed only a low affinity site. Zolpidem with affinity for alpha1, alpha2, and alpha3 subunits of GABA(A)/BZ receptor fully inhibited [(11)C]Ro15-4513 binding in the occipital cortex and cerebellum, while only about 23% of the binding was blocked in the anterior cingulate cortex. Diazepam with affinity for alpha1, alpha2, alpha3, and alpha5 subunits inhibited the binding in all brain regions. Since Ro15-4513 has relatively high affinity for the alpha5 subunit in vitro, these in vivo bindings of [(11)C]Ro15-4513 can be interpreted as the relatively high accumulation in the fronto-temporal limbic regions representing binding to the GABA(A)/BZ receptor alpha5 subunit.

Serotonin (5-HT) is considered to be an important transmitter underlying mood and behaviour. Abnormalities of the 5-HT transporter have been suggested in mood disorders, since it is one of the major binding sites of antidepressants. A number of ligands have been developed to visualise the 5-HT transporter in vivo, but only a few have successfully visualised specific binding in vivo. In this study, we comparatively evaluated two ligands for 5-HT transporter, [(11)C](+)McN5652 and [(11)C]cyanoimipramine, in the human brain. Brain uptake of [(11)C](+)McN5652 and [(11)C]cyanoimipramine was measured with PET in 15 healthy volunteers. Second PET scans were performed after pretreatment with the potent 5-HT reuptake inhibitor clomipramine. Data were analysed as regional brain uptake as well as whole brain uptake. In six healthy volunteers uptake of the two ligands was also measured in the lung since it is one of the high-uptake organs in the body. In the brain, high accumulation was observed in the thalamus and striatum, the regions known to contain high densities of 5-HT transporter, for both [(11)C](+)McN5652 and [(11)C]cyanoimipramine. The average ratio of thalamus to cerebellum uptake at 90 min after the tracer injection was approximately 1.6 for [(11)C](+)McN5652 and 1.7 for [(11)C]cyanoimipramine, while the ratios obtained after pretreatment with clomipramine were approximately 1.2. However, the whole brain uptake of [(11)C](+)McN5652 was approximately twice that of [(11)C]cyanoimipramine, while the lung uptake of [(11)C](+)McN5652 was approximately half that of [(11)C]cyanoimipramine. Both [(11)C](+)McN5652 and [(11)C]cyanoimipramine showed sufficient specific binding for performance of a quantitative analysis in the brain. [(11)C](+)McN5652 could be superior because of its higher distribution to the brain.

3-(4-Chlorobenzyl)-8-methoxy-1,2,3,4-tetrahydrochromeno[3,4- c ]pyridin-5-one (1), a putative dopamine D 4 receptor antagonist (k i = 8.7 nM), was labeled by positron-emitter ( 11 C) and its pharmacological evaluation was carried out with in vitro quantitative autoradiography and positron emission tomography (PET). 11 C-Methylation of a corresponding desmethyl precursor (2) with [ 11 C]CH 3 I gave [ 11 C]1 with ≥98% of radiochemical purity after HPLC purification and 67–90 GBq/μmol of specific activity at the end of synthesis. The in vitro autoradiography using rat brain sections demonstrated that [ 11 C]1 shows no specific binding to the D 4 receptors, but a high specific binding to sigma 1 receptors (IC 50 = 105 nM). In the PET study with monkey brain, [ 11 C]1 was highly taken up by the brain and trapped in the brain for at least 90 min. The distribution pattern of radioactivity in the brain was striatum > thalamus > frontal cortex > cerebellum, which was same as the result of in vitro autoradiography. Pre-treatment with non-radioactive 1 (1 mg/kg) produced a significant reduction of radioactivity in all the regions including the cerebellum. Pre-treatment with (+)pentazocine (1 mg/kg), a selective σ 1 receptor agonist, also reduced the radioactivity in the same regions to a similar extent. These results indicate that [ 11 C]1 may have some specific binding to the sigma 1 receptors, which is consistent with the result of in vitro autoradiography.

N -[ 18 F]Fluoroethyl-4-piperidyl acetate ([ 18 F]FEtP4A), an analog of [ 11 C]MP4A for mapping brain acetylcholineseterase (AchE) activity, was prepared by reacting 4-piperidyl acetate (P4A) with [ 18 F]fluoroethyl bromide ([ 18 F]FEtBr) using a newly developed automated system. Preliminary evaluation showed that the initial uptake of [ 18 F]FEtP4A in the mouse brain was > 8% injected dose/g tissue. The distribution pattern of [ 18 F]FEtP4A in the brain was striatum>cerebral cortex>cerebellum within 10–120 min post-injection, which reflected the distribution rank pattern of AchE activity in the brain. Moreover, chemical analysis of in vivo radioactive metabolites in the mouse brain indicated that 83% of [ 18 F]FEtP4A was hydrolyzed to N -[ 18 F]fluoroethyl-4-piperidinol ([ 18 F]FEtP4OH) after 1 min intravenous injection. From these results, [ 18 F]FEtP4A may become a promising PET tracer for mapping the AchE in vivo.

[11C](+)McN5652 is a selective serotonin reuptake inhibitor with subnanomolar potency for the serotonin transporter, and is currently being used for positron emission tomography studies. However, quantification of the regional [11C](+)McN5652 binding potential in vivo is a controversial issue because of its complex characteristics. The authors examined the regional differences in nonspecific binding and proposed simple methods for estimating the binding potential of [11C](+)McN5652. The regional difference in nonspecific binding was evaluated by the activity ratio of the thalamus compared with the cerebellum for inactive-isomer [11C](−)McN5652 and [11C](+)McN5652 saturation studies. The distribution volume of the thalamus was approximately 1.16 times larger than that of the cerebellum. The thalamus-to-cerebellum distribution volume ratio was estimated by nonlinear least square and graphical methods, with and without arterial input function. The graphical method with k2′ without blood sampling was practical and most applicable for estimation of the distribution volume ratio because this method is more stable than the nonlinear least square method in the simulation study. Binding potential estimated with the distribution volume ratio of [11C](+)McN5652 and the correction with distribution volume ratio of [11C](−)McN5652 represent the most reliable parameters for the assessment of serotonin transporter binding.

Two benzamide derivatives as dopamine D 4 receptor antagonists, YM-50001(4) and N - [2-[4-(4-chlorophenyl]piperizin-1-yl]ethyl]-3-methoxybenzamide (9), were labeled by positron-emitter ( 11 C), and their pharmacological specificities to dopamine D 4 receptors were examined by quantitative autoradiography and positron emission tomography (PET). Radiosyntheses were accomplished by O- methylation of corresponding phenol precursors (5 and 10) with [ 11 C]CH 3 I followed by HPLC purifications. In vitro binding on rat brain slices showed different distribution patterns and pharmacological properties between the two radioligands. The [ 11 C]4 showed the highest binding in the striatum, which was inhibited not only by 10 μM 4 but also by 10 μM raclopride, a selective dopamine D 2 receptor antagonist. In contrast, [ 11 C]9 showed the highest binding in the cerebral cortex, which was inhibited by several D 4 receptor antagonists (9, RBI-254, L-745,870), but not by any other receptor ligands (D 1 /D 5 , D 2 /D 3 , 5-HT 1A , 5-HT 2A , σ 1 and α 1 ) tested. In vivo brain distribution of [ 11 C]9 in rat showed the highest uptake in the frontal cortex, a region that has a high density of D 4 receptors. These results indicate that the pharmacological property of [ 11 C]9 matches the rat brain D 4 receptors, but that of [ 11 C]4 rather appears to match the rat brain D 2 receptors. The results for the benzamide [ 11 C]9 prompted us to further evaluate its potential as a PET radioligand for D 4 receptors by employing PET on monkey brain. Unfortunately, in contrast to rats, neither specific binding nor differences in regional uptake of radioactivity were observed in monkey brain after intravenous 11 C]9 injection. Based on that specific activities of radioligands might be critical in mapping the neurotransmitter receptors if they are only faintly expressed in the brain, 11 C]9 with an extremely high specific activity (1810 GBq/μmol) was used for PET study. However, the effort to determine the specific binding for D 4 failed. These results indicate that both of the benzamide derivatives would not be suitable radioligands for D 4 receptors with PET.

A new algorithm for digital image processing apparatuses is developed to evaluate profiles of high-intensity DC beams from temperature images of irradiated thin foils. Numerical analyses are performed to examine the reliability of the algorithm. To simulate the temperature images acquired by a thermographic camera, temperature distributions are numerically calculated for 20 MeV proton beams with different parameters. Noise in the temperature images which is added by the camera sensor is also simulated to account for its effect. Using the algorithm, beam profiles are evaluated from the simulated temperature images and compared with exact solutions. We find that niobium is an appropriate material for the thin foil used in the diagnostic system. We also confirm that the algorithm is adaptable over a wide beam current range of 0.11-214 μA, even when employing a general-purpose thermographic camera with rather high noise (ΔT(NETD) ≃ 0.3 K; NETD: noise equivalent temperature difference).

Solid-state materials suitable for use as proton irradiation targets were investigated for producing high-purity (11)CH4 molecules for heavy-ion cancer therapy. The radioactivity of gas produced by proton irradiation was measured for several target materials. Also, the radioactive molecular species of the produced gas were analyzed by radio gas chromatography. We found that 5 × 10(12) (11)C molecules could be collected by proton irradiation on a NaBH4 target. We also found that the (11)CH4 molecules were produced and collected directly from the irradiated target, owing to the hydrogen atoms bound in the solid-state NaBH4.

Extrastriatal D2 dopamine receptors represent an important target of research into the pathophysiology and pharmacotherapy of psychiatric disorders. The high affinity radioligand [11C]FLB 457 makes possible the measurement of low concentrations of D2 receptors in extrastriatal regions using positron emission tomography (PET). The aim of this study was to assess the test/retest variability and reliability of [11C]FLB 457 binding using a reference tissue model. Eight healthy male subjects (aged 20-33 years) underwent two [11C]FLB 457 PET examinations. Radioactivity in the cerebellum was used as the reference. The binding potentials (BPs) for five cortical regions of interest (ROIs) were calculated using the reference tissue model. The BP was also calculated for each pixel in the form of parametric images. Reproducibility was assessed both for the ROI method and for the parametric images. The test/retest reproducibility for [11C]FLB 457 binding was good, with a mean variability ranging from 4.5% for the thalamus to 15.5% for the hippocampus. The parametric images also demonstrated good reproducibility. These results support the suitability of using [11C]FLB 457 for the quantitative evaluation of extrastriatal D2 receptors and for protocols requiring repeated measurements in the same individual.

The aim of the present study was to quantify the density and affinity of human extrastriatal dopamine D2 receptors using positron emission tomography (PET). [(11)C]FLB-457, a high-affinity dopamine D2 receptor antagonist with various specific radioactivities (SA) was used. Eight healthy male subjects, age 20-35 yr, participated twice or three times at different SAs (1-279 GBq/ µmol), and serial dynamic scans were performed in the 3D data acquisition mode. The peak of the specific binding was not well defined with high SA due to the flatness of the curves after 60 min but was observed within the PET measurement. In the experiment with low SA, the peak came earlier than that with high SA. Scatchard analysis was performed using the maximal specific binding value (transient equilibrium) and the radioactivity in the cerebellum as free ligand concentration. The highest density was observed in the thalamus (2.3+/-0.6 pmol/ml), followed by the temporal cortex (1.5+/-0.5 pmol/ml), hippocampus (1.4+/-0.5 pmol/ml), parietal cortex (0.9+/-0.4 pmol/ml), frontal cortex (0.8+/-0.2 pmol/ml) and occipital cortex (0.7+/-0.3 pmol/ml). There was no significant difference in K(d) values in these six regions. The present results demonstrate that dopamine D2 receptor densities in the extrastriatal regions were only 2-8% of that in the striatum. Although the density of extrastriatal dopamine D2 receptor was low, significant regional differences were observed in the present study, as reported in postmortem studies.

4-Acetoxy derivative (1) of L-703, 717, a high-affinity (IC50=4.5 nM) antagonist for the glycine site of NMDA receptors, was synthesized and its brain uptake was examined using a carbon-11 labeled analog ([11C]1). Initial radioactivity in the brain after intravenous injection of [11C]1 was a 2-fold that of [11C]L-703, 717 in mice. Rapid bioconversion of [11C]1 into [11C]L-703, 717 was demonstrated by metabolite analyses of rat brain after [11C]1 injection. Ex vivo autoradiography of [11C]1 in rat brain showed the same cerebellar localization of radioactivity as [11C]L-703, 717. These results indicate that 1 is a promising pharmacological tool as a prodrug of L-703, 717 with improved BBB permeability.

The Watanabe heritable hyperlipidemic (WHHL) rabbit develops coronary atherosclerosis and hypercholesterolemia because of a genetic deficiency of low-density lipoprotein receptors and is therefore a good animal model for studying the relationships of coronary atherosclerosis, hypercholesterolemia and coronary flow reserve. The aim of the present study was to assess myocardial perfusion at baseline and during adenosine infusion (0.2 mg x kg(-1) x min(-1)) in 8 WHHL rabbits (13.8+/-0.5 months) with 13N-ammonia, small-animal positron emission tomography (PET) and colored microspheres. Results were compared with those from 6 age-matched Japanese white rabbits. Plaque distribution was also examined in the extramural coronary arteries. All 8 WHHL rabbits had coronary plaques, with 6 showing multiple plaques. Mean global myocardial blood flow (ml x min(-1) x g(-1)) did not differ significantly between control and WHHL groups both at baseline (3.67+/-0.72 vs 4.26+/-1.12 ml x min(-1) x g(-1), p=NS) and with adenosine (7.92+/-2.00 vs 9.27+/-2.91 ml x min(-1) x g(-1), p=NS), nor did coronary flow reserve (2.16+/-0.37 vs 2.18+/-0.41, p=NS). None showed evidence of regional perfusion abnormalities by visual and semiquantitative analyses of PET images. It was concluded that WHHL rabbits preserve adenosine-induced coronary flow reserve despite coronary atherosclerosis and hypercholesterolemia, suggesting that a compensatory mechanism develops in this animal model.

Personality is a behavioral pattern, which differs among individuals. Kretschmer (Kretschmer, E., Physique and Character: an Investigation of the Nature of Constitution and the Theory of Temperament, New York, 1921) categorized personality variants according to the concept of fundamental body types. Recently, several lines of evidence suggest that the central dopamine system may underlie the regulation of weight and the personality trait. In this study, we examined the dopamine D2 receptor (D2R) binding using positron emission tomography with [11C]FLB 457 [(s)-N-[(1-ethyl-2-pyrrolidinyl) methyl]-5-bromo-2,3-dimethyloxybenzamide] together with body mass index (BMI) and personality trait on the temperament and character inventory (TCI) in 16 normal subjects. Our data demonstrate that there was a significant relation among D2R binding in the amygdala, BMI and personality trait of harm avoidance. It can be assumed that variation of dopaminergic activity in the amygdala underlies the personality variants related to the concept of fundamental body type.

A positron-emitter labeled radioligand for the glycine-binding site of the N -methyl-d-aspartate (NMDA) receptor, [ 11 C]L-703,717, was examined for its ability to penetrate the brain in animals by simultaneous use with drugs having high-affinity separate binding sites on human serum albumin. [ 11 C]L-703,717 has poor blood–brain barrier (BBB) permeability because it binds tightly to plasma proteins. Co-injection of warfarin (50–200 mg/kg), a drug that binds to albumin and resembles L-703,717 in structure, dose-dependently enhanced the penetration by [ 11 C]L-703,717 in mice, resulting in a five-fold increase in the brain radioactivity at 1 min after the injection. Drugs structurally unrelated to L-703,717, salicylate, phenol red, and L-tryptophan, were less effective or ineffective in increasing the uptake of [ 11 C]L-703,717. These results suggest that the simultaneous use of a drug that inhibits the binding of a radioligand to plasma proteins is a useful way to overcome the poor BBB permeability of the radioligand triggered by its tight binding to plasma proteins. In brain distribution studies in rodents, it was found that, after the increase in brain uptake with warfarin, much of the glycine site antagonist accumulates in the cerebellum but its pharmacological specificity did not match the glycine site of NMDA receptors.

Anticholinergic drug is often used to treat extrapyramidal symptoms. We measured muscarinic cholinergic receptor (mAchR) occupancy by the oral administration of biperiden in eight healthy subjects using positron emission tomography (PET) and [ 11 C]N-methyl-4-piperidylbenzilate (NMPB). After the baseline scan each subject underwent one or two post-dose PET scans. mAchR occupancy was 10–45% in the frontal cortex three hours after the oral administration of 4mg of biperiden. The occupancy correlated with the plasma concentration of biperiden in a curvilinear manner.

The regional cerebral metabolic rate of [11C]N-methyl-4-piperidyl acetate, which is nearly proportional to regional cerebral acetylcholinesterase (AChE) activity, was measured by dynamic positron emission tomography in 20 healthy subjects with a wide age range (24-89 years). Quantitative measurement was achieved using a kinetic model which consisted of arterial plasma and cerebral tissue compartments. The plasma input function was obtained using thin-layer chromatography and an imaging phosphor plate system at frequent sampling intervals to catch the rapid metabolism of the tracer in the blood. The distribution of the rate constant k3, an index of AChE activity, agreed well with reported post-mortem AChE distribution oin the cerebral cortex (0.067-0.097 min-1) and thalamus (0.268 min-1), where AChE activity was low to moderate. The K3 values in the striatum and cerebellum, where AChE activity was very high, did not respond linearly to AChE activity because of increased flow dependency. No significant effect of age was found on AchE activity of hte cerebral cortex, suggesting that the ascending central cholinergic system is preserved in normal aging. This study has shown that quantitative measurement of enzyme activity in the living brain is possible through appropriate modelling of tracer kinetics and accurate measurement of hte input function. The method should be applicable to patients with Alzheimer's disease and those with other kinds of dementia whose central cholinergic system has been reported to be disturbed.

A fluorine-18 labeled analog of an antitumor prostaglandin delta 7-PGA1 methyl ester, 15-deoxy-13,14-dihydro-delta 7-PGA1 4-[18F]fluorobenzyl amide ([18F]3), was synthesized as a tracer candidate for detecting tumors with positron emission tomography. p-[18F]Fluorobenzylamine (p-[18F]FBnA) used as a labeled precursor for the synthesis of [18F]3 was prepared by fluorination of a 4-N, N, N-trimethylammonium-benzonitrile triflate with [18F]fluoride and subsequent reduction with borane-dimethylsulfide. Radiochemical yield and purity of p-[18F]FBnA obtained were 39-49% (decay uncorrected) and 91-96%, respectively, after C18 Sep-Pak purification. Treatment of p-[18F]FBnA with a 15-deoxy-13,14-dihydro-delta 7-PGA1 N-succinimidyl ester in acetonitrile and subsequent HPLC purification gave radiochemically pure (99%) [18F]3 with a 58% decay uncorrected yield. The total synthesis time was 70 min from the start of the radiosynthesis of p-[18F]FBnA.

11C-labeled cholecystokinin (CCK) receptor antagonists, 3R(+)-N-(2,3-dihydro-1-[11C]methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine- 3-yl)-N'-(3-methylphenyl)urea ([11C]L-365,260) and its (S)-enantiomer ([11C]L-365,346), have been synthesized and evaluated in vivo for use in CCK receptor studies with positron emission tomography (PET). Selective N-methylation of a racemic precursor with [11C]iodomethane and subsequent optical resolution of the racemate with HPLC afforded optically pure [11C]L-365,260 and [11C]L-365,346, which are selective for CCK-B (central-type) receptors and CCK-A (peripheral-type) receptors, respectively. Biodistribution studies in mice showed very low brain uptakes (

Acetylcholinesterase (AChE) activity in living human brain was characterized by determining the regional metabolic rate constant of a lipophilic acetylcholine analog, N-[11C]methylpiperidyl-4-acetate ([11C]MP4A). The metabolic rate constant is presumed to be proportional to the regional AChE activity in living human brain because of high specificity of [11C]MP4A for human cerebral AChE. Cerebral regional radioactivity data obtained from dynamic positron emission tomography were subjected to kinetic analyses based on a three-compartment model using the input function of arterial unchanged [11C]MP4A. Changes in fitting conditions gave varied rate constants of tracer uptake and washout. However, the metabolic rate constants were rather stable in various fitting conditions. The metabolic rate constants obtained in neocortical regions corresponded well with AChE activity obtained from postmortem studies, suggesting the feasibility of the present method for detection of changes in neocortical AChE activity in living human brain.

This study was performed to determine the effects of the angiotensin-converting enzyme inhibitor alacepril on hemodynamic variables and beta-adrenoceptor number in rabbits with heart failure induced by aortic regurgitation. Aortic regurgitation was induced by perforation of the aortic valve in 12 rabbits. Sixty mg/kg of alacepril was administered by gastric tube for 7 days after manifestation of aortic regurgitation to 6 rabbits (group AR + A). The other 6 rabbits with aortic regurgitation were administered vehicle in the same fashion (group AR + C). Seven rabbits underwent sham operation (group S). One week after induction of aortic regurgitation left ventricular end-diastolic pressure was higher and cardiac output was lower in AR + C than in S. End-diastolic and end-systolic left ventricular diameter were larger and left ventricular weight was also higher in AR + C than in S. For each of these parameters, the opposite findings were obtained from a comparison of AR + A and S. Myocardial beta-adrenoceptor density and norepinephrine content were reduced in AR + C, but were restored in AR + A. These findings indicate that alacepril has beneficial effects on ventricular remodeling and function, and on sympatho-neuronal regulation in the volume-overloaded myocardium.

A system for positron emission tomography study of conscious monkeys was newly developed. By use of this system in combination with a microdialysis technique, the effect of ketamine on the binding and release of dopamine was investigated. The administration of ketamine (5 mg/kg) caused sedation accompanied by psychotic symptoms such as nystagmus and stereotyped movements of extremities. During this psychotomimetic period produced by ketamine, a significant increase in the accumulation of the dopamine D2 receptor ligand N-[11C]methylspiperone was observed in the striatum compared with the level in the conscious state, while no significant change was observed in the frontal cortex and cerebellum. In contrast to the use of ketamine as the anesthetic, pentobarbital (25 mg/kg), which produced deeper anesthesia but no psychotic symptoms, caused a decrease in the accumulation of N-[11C]methylspiperone in the striatum. Kinetic analysis, conducted by a graphical method, revealed that the value of the association constant (K3) for N-[11C]methylspiperone binding in the striatum was increased to approximately 130% by ketamine and decreased to approximately 70% by pentobarbital compared with the control values. Furthermore, the release of dopamine from the striatum measured by microdialysis was not affected by ketamine anesthesia. These results indicate that ketamine facilitates striatal dopaminergic neurotransmission through increasing the binding activity of dopamine D2 receptors in the striatum, and suggest that these changes may be related to the psychotomimetic behavioral symptoms of this drug.

Ro15-4513, an azide derivative of benzodiazepine antagonist flumazenil (Ro15-1788), and Ro15-1788 were labelled with carbon 11. Sequential PET scans following injection of [11C]Ro15-4513 or [11C]Ro15-1788 into normal male healthy volunteers were measured, and kinetic analysis using pons as a reference region was performed. [11C]Ro15-4513 was highly accumulated in frontal cortex, temporal cortex, hippocampus and relatively lower accumulation in occipital cortex, whereas almost homogeneous distribution of Ro15-1788 throughout cortex area was seen. The kinetic analysis revealed that such differences of regional distribution in brain between two labelled ligands were mainly due to the regional difference of the dissociation rate constants in vivo (k4). [11C]Ro15-4513 may be a useful tool for the in vivo study of benzodiazepine receptors in human brain.

The recent development of a high resolution positron emission tomography and appropriate radioligands labelled with positron emitter has made it possible to clearly delineate distribution of neuroreceptors in the human brain.

Background The clinical efficacy of dopamine D 2 receptor antagonism on the psychotic symptoms of schizophrenia has been widely demonstrated. However, most in vivo imaging studies have not been able to detect significant changes in striatal D 2 receptors in schizophrenia. On the other hand, a number of studies have reported abnormalities in the cerebral cortex of schizophrenia. The aim of this study was to examine the extrastriatal D 2 receptors of patients with schizophrenia. Methods Eleven drug-naive male patients with schizophrenia were examined with positron emission tomography using carbon 11–labeled FLB 457. Symptoms were assessed using the Brief Psychiatric Rating Scale. Eighteen healthy controls were used for comparison. Region-of-interest analysis was performed using the reference tissue method, and binding potential (BP) was used for the index of dopamine D 2 receptor binding. Results The BP value was significantly lower, by about 12.5%, in the anterior cingulate cortex in drug-naive patients with schizophrenia than in healthy controls. A significant negative correlation was observed between BP in the anterior cingulate cortex and the positive symptom score on Brief Psychiatric Rating Scale. Conclusions The lower BP values indicate fewer D 2 receptors in the anterior cingulate cortex in patients with schizophrenia. Alterations in D 2 receptor function in the extrastriatal region may underlie the positive symptoms of schizophrenia.