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This study was aimed to assess the correlations among α7 nicotinic acetylcholine receptor (α7-nAChR) binding, amyloid-β (Aβ) deposition, and mitochondrial complex I (MC-I) activity in the brain of aged monkeys (Macaca mulatta). Positron emission tomography (PET) measurements with [(11) C](R)-MeQAA, [(11) C]PIB, and [(18) F]BCPP-EF were conducted in monkeys in a conscious condition. [(11) C](R)-MeQAA binding was analyzed by a simplified reference tissue model to calculate nondisplaceable binding potential (BPND), [(11) C]PIB uptake was calculated by standard uptake value ratio (SUVR), and [(18) F]BCPP-EF binding was determined by Logan graphical analysis to calculate total distribution volume (VT) with arterial blood sampling. Higher brain uptake was determined in the thalamus, hippocampus, striatum, and cortical regions for [(11) C](R)-MeQAA, while being lower in the cerebellum. Significant age-related reduction of [(11) C](R)-MeQAA binding to α7-nAChR was determined only in the occipital cortex. The plot of Vt of [(18) F]BCPP-EF against BPND of [(11) C](R)-MeQAA indicated a significant negative correlation in the hippocampus and cortical regions in aged animals. Plotting of SUVR of [(11) C]PIB against BPND of [(11) C](R)-MeQAA showed a positive correlation. The in vivo binding of [(11) C](R)-MeQAA could reflect the upregulation of α7-nAChR induced by neurodegenerative damage determined by Aβ deposition as well as impaired MC-I activity in living brain.

Carbon-11-labeled (R,R)trans-8-methyl-2-hydroxy-3-[4-[2-aminophenyl]piperizinyl]-tetralin ([(11)C](R,R)HAPT) and its stereoisomer [(11)C](S,S)HAPT were developed for imaging vesicular acetylcholine transporters (VAChTs), exclusively located in presynaptic cholinergic neurons. Both positron emission tomography (PET) probes were evaluated in the brain of conscious monkey (Macaca mulatta) using high-resolution PET. Time-activity curves (TACs) of [(11)C](R,R)HAPT peaked within 5 min after the injection in all regions except the caudate and putamen, both of which showed peaks around 20 min postinjection. The regional distribution patterns of [(11)C](R,R)HAPT determined as total distribution volume (V(t)) were highest in the putamen, high in the caudate, intermediate in the amygdala, hippocampus, and thalamus, lower in the cingulate gyrus and frontal, temporal, and occipital cortices, and lowest in the cerebellum. In contrast, the distribution and TACs of [(11)C](S,S)HAPT were homogeneous in all regions. The uptake of [(11)C](R,R)HAPT was reduced by 1 mg/kg (-)-vesamicol, a specific VAChT antagonist, in all regions except the cerebellum, but not by 0.1 mg/kg SA4503, a specific sigma-1 receptor agonist. These results well reflect the in vitro affinity assessments using rat cerebral membranes. They also demonstrate that [(11)C](R,R)HAPT is a potential PET probe for noninvasive and quantitative imaging of VAChT in the living brain.

The acute and subacute ischemic neuronal damage in rat brain caused by photochemically induced thrombosis (PIT) was imaged using [¹⁸F]BMS-747158-02 ([¹⁸F]BMS) for mitochondrial complex-1 (MC-1) and [¹¹C](R)-PK11195 ([¹¹C](R)-PK) for peripheral benzodiazepine receptor [PBR; translocator protein] at preischemic "Normal," 1 (day 1), and 7 days (day 7) after ischemic insult. When [¹⁸F]BMS was intravenously injected into "Normal" rat, it was rapidly taken up into the brain, in which it showed a homogeneous distribution, and the uptake was suppressed by rotenone, a specific MC-1 inhibitor. The specificity of [¹⁸F]BMS binding to MC-1 was also confirmed by living brain slice imaging. At day 1, [¹⁸F]BMS uptake was low in infarct and peri-infarct regions where neuronal damage was detected by 2,3,5-triphenyltetrazolium chloride (TTC) staining. At day 7, the damaged areas determined using [¹⁸F]BMS revealed some discrepancy from those detected by TTC staining, suggesting that TTC stained not only surviving cells but also activated microglial cells in the peri-infarct region. This was also confirmed by [¹¹C](R)-PK imaging and immunohistochemical assessment with Iba1 antibody. In contrast, the uptake pattern of [¹⁸F]BMS was consistent with immunohistochemical assessment with NeuN antibody at both days 1 and 7. These results demonstrated that [¹⁸F]BMS could be a promising positron emission tomography ligand to assess the neuronal damage induced by ischemic insult in both acute and subacute phases.

N-[¹¹C]methyl-3-piperidyl benzilate ([¹¹C]+3-MPB) was developed as a positron emission tomography (PET) ligand for muscarinic cholinergic receptor (mAChR). The aim of the present study was to validate a Logan reference tissue method as an analytical method for in vivo binding of [¹¹C]+3-MPB to mAChR. Seven monkeys (Macaca mulatta) underwent [¹¹C]+3-MPB PET scans with an arterial blood sampling. Logan plot with arterial input function (Logan arterial input method) was performed to determine the binding potential (BP(ND)). The BP(ND) was also determined by Logan plot with the cerebellum as the reference region (Logan reference tissue method). BP(ND) values determined by Logan arterial input method and Logan reference tissue method showed a significant linear relationship. The present study suggests that the cerebellum is a suitable reference region for quantification of mAChR in the living brain with [¹¹C]+3-MPB and PET.

(-)-o-Methylvesamicol ((-)-OMV) exhibited in vitro a high affinity for a vesicular acetylcholine transporter (VAChT) (Ki, 6.7 nM), and (-)-o-[(11)C]methylvesamicol [(-)-[(11)C]OMV] exhibited appropriate kinetics and bound mainly to VAChTs in the rat brain. In this study, the in vivo distribution and kinetics of (-)-[(11)C]OMV were evaluated in comparison with [(11)C]SA4503 in disability model monkeys produced by selectively destroying the p75NTR-positive cells in the right hemisphere of the brain using positron emission tomography. Time-activity curves of (-)-[(11)C]OMV showed peaks within 20 min in regions rich in acetylcholine transporters (AchT). (-)-[(11)C]OMV binding in the ipsilateral cortex to the lesion was significantly reduced by 22.0% +/- 6.7% when compared with that in the contralateral region. The decrease (19.3% +/- 2.2%) in (-)-[(11)C]OMV binding in the ipsilateral temporal cortex to the lesion was greater than that (7.4% +/- 4.6%) of [(11)C]SA4503. These results suggested that (-)-[(11)C]OMV may be useful in the study of dementia characterized by degeneration of the cholinergic neurotransmitter system.

[11C]PIB and [18F]FDDNP were examined on five aged and five young adult male rhesus macaques using positron emission tomography. Both tracers showed increased accumulation in the striatum, thalamus, cingulate and pons in the aged group. Compared to [11C]PIB, [18F]FDDNP showed higher accumulation in the cortical regions of aged animals as well as young animals. Although [18F]FDDNP may have possible usefulness for imaging, including other proteins, [11C]PIB may be better for amyloid imaging owing to lower non-specific binding. Synapse 62:472–475, 2008. © 2008 Wiley-Liss, Inc.

[(18)F]MPPF is a selective and reversible antagonist to the serotonin-1A (5-HT(1A)) receptor. The aim of the present study was to investigate whether the binding of [(18)F]MPPF is sensitive to increases in 5-HT levels. We used the 5-HT releasing agent and reuptake inhibitor fenfluramine (FEN) to increase the concentration of 5-HT. [(18)F]MPPF binding was assessed using positron emission tomography (PET) in conscious monkeys. Possible effects of blood flow on ligand binding were excluded by using a bolus-infusion paradigm. Control scans were obtained to assess the state of ligand equilibrium. FEN (5 or 10 mg/kg, i.v.) was administered between 90 and 130 min after the start of the [(18)F]MPPF infusion. The binding potential (BP) was calculated for an early interval (30 min preceding FEN administration) and late interval (20-50 min after administration of FEN). Microdialyses results showed a 20- and 35-fold increase in extracellular 5-HT levels in the prefrontal cortex after injection of FEN at a dose of 5 mg/kg and 10 mg/kg respectively. However, despite these large increases in 5-HT levels, no differences in BP were found between the control and FEN scans. These results may imply that the majority of 5-HT(1A) receptors is in the low affinity state in the living brain.

Rat striatum was microinjected with 50 nmol sodium nitroprusside (SNP) and neural cell death as well as the binding of dopaminergic receptors were followed for 24 h after the infusion using TTC staining, cresyl violet staining, and quantitative autoradiography. Striatal cell death was observed 3 h after the infusion of SNP. A widespread area of cell death, including part of the cerebral cortex, was seen at 24 h after the infusion. A decrease of more than 80% in dopamine D1 receptor binding was seen in rat brain slices prepared 2 h after the infusion of SNP, whereas only a slight decrease in dopamine D2 receptor binding and almost no changes in dopamine transporter binding were observed. One day after the infusion, less than 10% of the binding of all three types of dopaminergic receptors remained in a widespread area in the infused side of the striatum and part of the cerebral cortex. Microinjection of either NOC-18 (50 nmol), another type of NO donor, or sodium cyanide (50 nmol) did not caused cell death. In addition, microinjection of FeCl2 (50 nmol) into the striatum caused cell death and reduction in dopamine D1 receptor binding. These results suggest that iron-related radical reactions, but not NO itself, might have important roles on SNP-caused cell death. The current receptor binding study also indicated that dopamine D1 receptor binding is the most sensitive indicator for detection of cell death or cell damage induced by radical reactions in the rat striatum. Synapse 50:137–143, 2003. © 2003 Wiley-Liss, Inc.

Although a very large literature exists on the in vitro, ex vivo, and in vivo effects of nicotine on dopamine release in rodents, similar data in primates are scant. This study was initiated to compare methamphetamine to nicotine given i.v. to normal unanesthetized monkeys using positron emission tomography (PET) techniques. Release of dopamine in the striatum using [11C]raclopride was determined indirectly in four nicotine-naive adult Macaca mulatta monkeys under conscious and isoflurane-anesthetized conditions using high-resolution PET. [11C]Raclopride was given i.v. as a bolus injection followed by continuous infusion with steady state over 30–45 min. Nicotine bitartrate was then given as a bolus plus infusion for 30 min in doses of 32 μg/kg + 0.8 μg/kg/min or 100 μg/kg + 2.53 μg/kg/min as base. The larger doses of nicotine caused significant cardiovascular effects; these doses did not displace [11C]raclopride binding in either dorsal or ventral striatum under the anesthetized conscious condition. In contrast, isoflurane-anesthesia induced a slight but significant dose-dependent reduction of [11C]raclopride binding by nicotine even at the same doses used in the anesthetized condition. Methamphetamine in bolus doses of 0.1, 0.3, and 1.0 mg/kg i.v. under conscious condition caused a significant displacement of [11C]raclopride and isoflurane-anesthesia facilitated the displacement induced by nicotine. These results indicate that nicotine, in high tobacco-smoking-related doses, does not release sufficient brain dopamine to displace [11C]raclopride in the striatum in the awake and fully conscious state, in contrast to small doses of methamphetamine. Synapse 45:207–212, 2002. © 2002 Wiley-Liss, Inc.

In the present study, age-related changes in the striatal dopaminergic system were examined in the living brains of conscious young (6.2 +/- 1.5 years old) and aged (20.2 +/- 2.6 years old) monkeys (Macaca mulatta) using positron emission tomography (PET). L-[beta-(11)C]DOPA and [(11)C]beta-CFT were applied to determine dopamine presynaptic functions such as synthesis rate and transporter (DAT) availability, respectively. Striatal dopamine D(1)- (D(1)R) and D(2)-like receptor (D(2)R) binding were measured with [(11)C]SCH23390 and [(11)C]raclopride, respectively. Although the markers of presynaptic terminals showed parallel age-related declines, the reduction of dopamine synthesis rate measured with L-[beta-(11)C]DOPA was slightly smaller than that of DAT determined with [(11)C]beta-CFT. The binding of [(11)C]raclopride to D(2)R in vivo was significantly reduced with aging, while that of [(11)C]SCH23390 to D(1)R showed no such marked age-related reduction. When the DAT inhibitor GBR12909 (0.5 and 5 mg/kg) was administered, DAT availability, dopamine synthesis, and D(2)R binding were significantly decreased in a dose-dependent manner in both age groups; however, the degrees of the decreases in these parameters were significantly higher in young rather than in aged animals. Dopamine concentration in the striatal extracellular fluid (ECF), as measured by microdialysis, was increased by administration of GBR12909 in a dose-dependent manner and the degree of the increase in dopamine level decreased with age. These results demonstrate that age-related changes of dopamine neuronal functions were not limited to the resting condition but were also seen in the functional responses to the neurotransmitter modulation.

The present study demonstrated the age-related changes in the striatal dopamine D1 receptor binding and its related cAMP second-messenger system in the living brains of conscious young (6.4 +/- 1.8 years old) and aged (19.5 +/- 3.3 years old) monkeys (Macaca mulatta) using positron emission tomography (PET). For quantitative analysis of D1 receptors, [11C]SCH23390 was used and phosphodiesterase type-IV (PDE-IV) activity, as an index of cAMP system, was estimated by two scans with R- and S-[11C]rolipram. Significant age-related decreases in D1 receptor binding were observed in the striatum and frontal cortex. Analysis of uptake of R- and S-[11C]rolipram indicated age-related decreases in PDE-IV activity showing 22.0 and 25.2% decreases in the striatum and frontal cortex, respectively, while no significant changes were observed in the cerebellum. With systemic preadministration of the dopamine D1 receptor antagonist SCH23390 (0.2, 0.6, and 2 mg/kg), the PDE-IV activities in the striatum and frontal cortex were dose-dependently suppressed in both age groups. However, the degree of suppression by SCH23390 was more marked in young than in aged monkeys. These results demonstrate that the striatal cAMP second-messenger system activity as well as its functional response to dopamine D1 antagonist showed age-related impairment in the brain.

The effects of ketamine anesthesia on the binding of [(11)C]-labeled cocaine analogs, [(11)C]beta-CFT (2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane) and [(11)C]beta-CIT-FE (N-(2-fluoroethyl)-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane), to the striatal dopamine transporter (DAT) were evaluated in the monkey brain using positron emission tomography (PET). We sequentially measured the kinetics of these labeled compounds in the brains of five young-adult male rhesus monkeys (Macaca mulatta) in the conscious state, followed by those under ketamine anesthesia with continuous infusion (3 and 10 mg/kg/h). After intravenous injection, [(11)C]beta-CFT and [(11)C]beta-CIT-FE were predominantly accumulated in the striatum in both conscious and ketamine-anesthetized states. In the conscious state, the striatal uptake of [(11)C]beta-CFT and [(11)C]beta-CIT-FE continuously increased with time up to 91 min after injection. Continuous infusion of ketamine-induced higher levels of uptake of [(11)C]beta-CFT and [(11)C]beta-CIT-FE into the brain in a dose-dependent manner as compared with conscious state, and kinetic analysis with metabolite-corrected arterial input function indicated that the binding potentials (BP = k(3)/k(4)) of both compounds were elevated by ketamine. Not only [(11)C]beta-CIT-FE but also [(11)C]beta-CFT reached the equilibrium state of specific binding in the striatum within 40-50 min after injection. The present results demonstrated that ketamine significantly alters the DAT availability as measured with [(11)C]beta-CFT and [(11)C]beta-CIT-FE in the brain.

The present study evaluated the effects of methamphetamine and scopolamine on the striatal dopamine D1 receptor binding, measured by [11C]SCH23390, and D1 receptor-coupled cAMP messenger system, determined as phosphodiesterase type-IV (PDE-IV) activity, were evaluated in the brains of conscious monkeys using positron emission tomography (PET) with microdialysis. When methamphetamine (0.1, 0.3, and 1 mg/kg) or scopolamine (0.01, 0.03, and 0.1 mg/kg) was systemically administered, [11C]SCH23390 binding to D1 receptors was not affected. With administration of methamphetamine, the striatal PDE-IV activity, as measured with R-[11C]rolipram (active form) and S-[11C]rolipram (inactive form), was dose-dependently facilitated with enhanced dopamine level in the striatal ECF. Administration of scopolamine also induced facilitated PDE-IV activity without any apparent changes in the ECF dopamine. These facilitations of PDE-IV activity were abolished by preadministration of SCH23390, but not by raclopride. These results demonstrate that, as evaluated by PDE-IV activity, the inhibition of muscarinic cholinergic receptors actually facilitated dopamine neuronal signal transduction through D1 receptors, as observed previously on D2 receptors with no apparent increase in the striatal ECF dopamine level, but the enhanced dopamine transmission could not detected by [11C]SCH23390. Synapse 42:258–265, 2001. © 2001 Wiley-Liss, Inc.

Age-related changes in the serotonin transporter (SERT) in the living brains of conscious young (5.9 +/- 1.8 years old) and aged (19.0 +/- 3.3 years old) monkeys (Macaca mulatta) were evaluated in combination with [(11)C](+)McN5652 and its inactive enantiomer [(11)C](-)McN5652 by high-resolution positron emission tomography (PET). For the quantitative analysis of SERT binding in vivo, two serial PET scans with [(11)C](+)McN5652 and [(11)C](-)McN5652 were performed in the same animals in a day and the differences in radioactivities of [(11)C](+)McN5652 vs. [(11)C](-)McN5652 measured from 41-91 min postinjection were calculated as an estimate of specific ligand binding. Higher specific binding of SERT was observed in the thalamus and striatum, regions known to contain high densities of SERT by in vitro assay, with intermediate levels in the pons, hippocampus, cingulate gyrus, and cortical regions and lower levels in the cerebellum in both young and aged monkeys. Almost all regions assayed except the cerebellum showed significant age-related decreases in the specific binding of SERT, which showed reverse correlation with cortisol level in plasma. When the SERT blocker fluvoxamine (1 mg/kg) was administered intravenously 30 min after tracer injection, specific binding of SERT was displaced in both age groups. However, the degree of displacement was more marked in young than in aged monkeys. Cortisol level in plasma was significantly higher in aged than in young animals. These observations demonstrate the usefulness of the combined use of [(11)C](+)McN5652 and [(11)C](-)McN5652 as an indicator for the age-related changes in cortical SERT measured noninvasively by PET. In addition, these observations suggest that the age-related impairment of SERT sensitivity for fluvoxamine might be related to the reduced efficacy of antidepressant therapy in elderly patients with depression.