Toward a biochemistry of mind?

Small-animal positron emission tomography as a tool for neuropharmacology

Several post-mortem studies have identified increases of 5-HT1A receptor density in frontal cortical areas in schizophrenic patients, and one has found increases in the cerebellar vermis. Clozapine has moderate affinity at the 5-HT1A receptor, and this may be of therapeutic importance. This positron emission tomography (PET) study attempted to replicate the post-mortem findings in vivo and sought an occupancy effect of clozapine at the 5-HT1A receptor. We recruited healthy controls, and patients with schizophrenia who were divided into those receiving clozapine and those receiving neuroleptics lacking 5-HT1A receptor affinity. Each volunteer received a PET scan, using the 5-HT1A receptor radioligand [carbonyl-11C]WAY-100635, and a magnetic resonance imaging scan. The cerebellar vermis was examined by comparing time-activity data between groups. For other brain regions (the raphe and subdivisions of the cerebral cortex), binding potential images were generated to reflect receptor density, then analysed using 'region of interest' and voxel-by-voxel methods. No significant changes of 5-HT1A receptor density were found in schizophrenic patients compared to controls. Two other PET studies, containing drug naïve rather than medicated schizophrenic patients, have also reported no increase in 5-HT1A receptor density in the frontal cortex. The results obtained in vivo bring into question the importance of the receptor in the pathophysiology of the illness. Clozapine did not occupy the 5-HT1A receptor at clinical doses. This is consistent with recent related PET results: 5-HT1A agonists do not appear to measurably block the binding of antagonist radiotracers in man at doses that are pharmacologically active but which are limited by tolerability.

A wide array of positron emission tomography (PET) ligands have been developed that provide information relevant to multiple aspects of addiction (1-3).Locations of targets are approximated on this diagram, which is color-coded by functional roles.On the presynaptic side (pink), targets include neurotransmitter precursors (orange, example [ 18 F]-fluorodopa, FDOPA), modulatory receptors (yellow, examples [ 11 C] GR103545, [ 11 C] LY27950509 and [ 18 F] LY2459989 for kappa opioid receptors, KOR; [ 18 F]FMPEP for cannabinoid 1 receptors, CB1), and neurotransmitter reuptake transporters (light green, examples [ 11 C] PE2I and [ 18 F] FE-PE2I for the dopamine transporter, DAT).On the postsynaptic side (purple), targets include neurotransmitter receptors (blue, examples [ 11 C] raclopride and [ 11 C]-(1)-PHNO for dopamine D 2 and D 3 receptors, D 2 R; [ 11 C] carfentanil for mu opioid receptors, MOR; [ 18 F] LY2459989 for both mu and kappa opioid receptors; 2-[ 18 F]fluoro-3-(2(S)-azetidinylmethoxy) pyridine for nicotinic acetylcholine receptors, nAChR).Some PET ligands target more generic functions.[ 18 F]-fluoro-deoxy-glucose (FDG) PET provides a measure of cerebral metabolic rate.

In most parts of the world, alcohol is consumed for social and recreational reasons. However, the initially controllable use can become compulsive and alcohol dependence develops. Late dependence is characterized by persistent neuroadaptations in various brain neurotransmitter systems, including the endogenous opioid and dopamine system, which are thought to underlie relapse. Many hypotheses on the state of brain neurotransmitter systems are based on positron emission tomography (PET) studies. However, the interpretation of those data is challenging as PET signals are sensitive not only to receptor but also ligand levels. For instance, increased μ-opioid receptor (MOR) PET binding potentials are interpreted as elevated receptor levels. Those are thought to be the target of the anti-relapse medication naltrexone, an opioid antagonist. However, naltrexone’s effect size is relatively small and only a subset of alcohol-dependent patients appears to benefit. Furthermore, only few studies on the opioid and dopamine system during protracted abstinence are available. This is surprising as this phase is characterized by high relapse propensity and, thus, is clinically highly relevant. Therefore, this thesis aims to demonstrate the state of the opioid and dopamine system during alcohol abstinence. A translational approach was applied by analyzing these systems in four separate studies (Study I-IV) in post-mortem brain tissue of human alcoholics and an animal model of alcohol dependence. In Study I, transcriptional and protein levels (receptor binding sites) of the MOR are found to be strongly reduced in the striatum of alcoholics. Additionally, a PET study associates decreased striatal MOR binding potential with higher relapse risk. Decreased MOR expression is mirrored by data from alcohol-dependent rats in Study II. Furthermore, the precursor of the MOR-ligand β-endorphin Pomc is significantly reduced. Signaling at the δ-opioid receptor (DOR) appears to be decreased in alcohol dependence while the κ-opioid receptor (KOR) system is upregulated. In Study III, chronic naltrexone treatment counteracts the changes in MOR/Pomc levels by significantly increasing expression and further enhanced KOR density. The DOR, in contrast, seems not to be a target of naltrexone under the applied experimental conditions. Because the endogenous opioid system is known to modulate dopamine release, the dopamine system was investigated in Study IV. Here, human post-mortem tissue reveals strongly decreased dopamine transporter and D1 receptor levels in alcoholics while D2 is unchanged. These findings are further supported by the alcohol-dependent animals where an oscillatory-like regulation of the dopamine system is observed during acute withdrawal and protracted abstinence. While previous studies report on a hypodopaminergic state during acute withdrawal, here, a hyperdopaminergic state is demonstrated during protracted abstinence by measurements of striatal dopamine release and a meta-analysis followed by functional validations. Based on these data, both hypo- and hyperdopaminergic states are suggested as phases with increased vulnerability for alcohol relapse. In summary, the results presented in this thesis provide consistent evidence for a severe dysregulation of the endogenous opioid and dopamine system during alcohol abstinence that demands reinterpretation of existing PET data. It is proposed for future studies to combine the analysis of human post-mortem tissue and established animal models with PET studies to achieve a more precise picture of the state of brain neurotransmitter systems in alcoholic patients. Moreover, decreased MOR and dopamine receptor/transporter levels may represent molecular markers of the disease course that can be used to develop personalized treatment approaches.

[N-methyl-11C]alpha-Methylaminoisobutyric acid (11C-MeAIB) is a potentially useful tracer for positron emission tomography (PET) studies on hormonally regulated system A amino acid transport. 11C-MeAIB is a metabolically stable amino acid analogue specific for system A amino acid transport. We evaluated the biodistribution of 11C-MeAIB in rats and humans to estimate the usefulness of the tracer for in vivo human PET studies, for example, on regulation of system A amino acid transport and on tumour imaging. Healthy Sprague-Dawley rats (n=14) were killed 5, 20, 40 or 60 min after the injection of 11C-MeAIB, and the tissue samples were weighed and counted for 11C radioactivity. Ten lymphoma patients with relatively limited tumour burden underwent whole-body (WB) PET imaging with 11C-MeAIB. In addition, three other patients had dynamic PET scanning of the head and neck area, and the tracer uptake was quantitated by calculating the kinetic influx constants (Ki values) for the tracer. In animal studies, the highest activity was detected in the kidney, pancreas, adrenal gland and intestines. In humans, the highest activity was found in the salivary glands, and after that in the kidney and pancreas, similar to the results in animal studies. Rapid uptake was also detected in the skeletal muscle. In the graphical analysis, linear plots were obtained, and the mean fractional tracer uptake values (Ki) of the parotid glands (n=3) and cervical muscles (n=3) were 0.039+/-0.008 min(-1) and 0.013+/-0.006 min(-1), respectively. The Ki value of the tumour (n=1) was 0.064 min(-1). Higher uptake of 11C-MeAIB into the tumour tissue was encountered. These results encourage further 11C-MeAIB PET studies in humans on the physiology and pathology of system A amino acid transport and on tumour detection.

Knowledg of the precision in the physiological parameters estimated by positron emission tomography (PET) is helpful for optimizing PET study and accurate diagnosis. Nonparametric bootstrap method proposed by Buvat is re- sampling techniques that can be used to accurately estimate the statistical properties of PET images in one scan and determine statistics of pixel values. The standard deviation (SD) of time activity curves (TAC) generated by region of interests (ROI) also are estimated by using the bootstrap method and the SD would propagate to estimated parameters such as blood flow. In order to evaluate the present method, a PET study for myocardial blood flow (MBF) measurement with H2 15 O_PET was performed. The statistical properties of MBF were estimated and the effects of scan-duration time and ROI size on the SD of MBF were developed. statistical properties of PET images in a single scan. The bootstrap approach is a computer-based statistical method for determining the accuracy of a statistic from experimental data (6). Buvat estimated statistical properties for PET and single photon emission computed tomography (SPECT) successfully using non-parametric bootstrap method (7). Noise estimates in reconstructed images could be introduced into quantitative data analysis to account for the uncertainty of pixel and region of interest (ROI) values. This study investigated the precision in the MBF with H2 15 O_PET using statistical properties expressed by bootstrapped images of a single acquisition. Using the concept of the non-parametric bootstrap method, we developed a method to know the standard deviation (SD) and coefficient of variation (COV) of estimated parameters of MBF, PTF, and arterial blood volume with H2 15 O_PET. A PET study with one pig was performed in order to evaluate the present technique. Strategies for scan duration and ROI selection were also investigated with the effect of SD and COV indicated by present method.

The purpose of this study was to compare the results of perfusion computed tomography (PCT) with those of (15)O(2)/H(2) (15)O positron emission tomography (PET) in a subset of Carotid Occlusion Surgery Study (COSS) patients. Six patients enrolled in the COSS underwent a standard-of-care PCT in addition to the (15)O(2)/H(2) (15)O PET study used for selection for extracranial-intracranial bypass surgery. PCT and PET studies were coregistered and then processed separately by different radiologists. Relative measurement of cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were calculated from PET. PCT datasets were processed using different arterial input functions (AIF). Relative PCT and PET CBF values from matching regions of interest were compared using linear regression model to determine the most appropriate arterial input function for PCT. Also, PCT measurements using the most accurate AIF were evaluated for linear regression with respect to relative PET OEF values. The most accurate PCT relative CBF maps with respect to the gold standard PET CBF were obtained when CBF values for each arterial territory are calculated using a dedicated AIF for each territory (R (2) = 0.796, p < 0.001). PCT mean transit time (MTT) is the parameter that showed the best correlation with the count-based PET OEF ratios (R (2) = 0.590, p < 0.001). PCT relative CBF compares favorably to PET relative CBF in patients with chronic carotid occlusion when processed using a dedicated AIF for each territory. The PCT MTT parameter correlated best with PET relative OEF.

Canine myocardial dihydropyridine binding sites: A positron emission tomographic study with the calcium channel inhibitor 11C-S11568

Reproducibility of in vivo brain measures of 5-HT2A receptors with PET and [ 18F]deuteroaltanserin

BackgroundDysfunction of the glycine transporter 1 (GlyT1) has been suggested to be involved in psychiatric disorders such as schizophrenia. GlyT1 inhibitors have therefore been considered to have antipsychotic therapeutic potential. Positron emission tomography (PET) imaging probes for GlyT1 are, consequently, expected to be useful for investigating the mechanism of such disease conditions and for measuring occupancy of GlyT1 inhibitors in vivo. The aim of this study was to assess the potential of 2-chloro N-[(S)-{(S)-1-[11 C]methylpiperidin-2-yl} (phenyl)methyl] 3-trifluoromethyl-benzamide ([11 C]N-methyl-SSR504734) as a PET imaging agent for GlyT1.Methods[11 C]N-methyl-SSR504734 was synthesized by N-[11 C]methylation of SSR504734 via [11 C]CH3OTf. In vitro brain distribution of [11 C]N-methyl-SSR504734 was tested in whole-hemisphere autoradiography (ARG) on human brain slices. Initial PET studies were performed using a cynomolgus monkey at baseline and after pretreatment with 0.1 to 1.5 mg/kg of SSR504734. Then, PET studies using rhesus monkeys were performed with arterial blood sampling at baseline and after pretreatment with 1.5 to 4.5 mg/kg SSR504734. Distribution volumes (VT) were calculated with a two-tissue compartment model, and GlyT1 occupancy by SSR504734 was estimated using a Lassen plot approach.Results[11 C]N-methyl-SSR504734 was successfully synthesized in moderate radiochemical yield and high specific radioactivity. In the ARG experiments, [11 C]N-methyl-SSR504734 showed specific binding in the white matter and pons. In the initial PET experiments in a cynomolgus monkey, [11 C]N-methyl-SSR504734 showed high brain uptake and consistent distribution with previously reported GlyT1 expression in vivo (thalamus, brainstem > cerebellum > cortical regions). However, the brain uptake increased after pretreatment with SSR504734. Further PET studies in rhesus monkeys showed a similar increase of brain uptake after pretreatment with SSR504734. However, the VT of [11 C]N-methyl-SSR504734 was found to decrease after pretreatment of SSR504734 in a dose-dependent manner. GlyT1 occupancy was calculated to be 45% and 73% at 1.5 and 4.5 mg/kg of SSR504734, respectively.Conclusions[11 C]N-methyl-SSR504734 is demonstrated to be a promising PET radioligand for GlyT1 in nonhuman primates. The present results warrant further PET studies in human subjects.

Radioligand positron emission tomography (PET) with dual scan paradigms can provide valuable insight into changes in synaptic neurotransmitter concentration due to experimental manipulation. The residual t-test has been utilized to improve the sensitivity of the t-test in PET studies. However, no further development of statistical tests using residuals has been proposed so far to be applied in cases when there are more than two conditions. Here, we propose the residual f-test, a one-way analysis of variance (ANOVA), and examine its feasibility using simulated [11C]raclopride PET data. We also re-visit data from our previously published [11C]raclopride PET study, in which 10 individuals underwent three PET scans under different conditions. We found that the residual f-test is superior in terms of sensitivity than the conventional f-test while still controlling for type 1 error. The test will therefore allow us to reliably test hypotheses in the smaller sample sizes often used in explorative PET studies.

The Japanese language has three writing systems: kanji script, or ideograms, hiragana script, or phonograms and katakana script, another type of phonograms. Modern Japanese has 71 hiragana and 71 katakana characters, which have one-to-one correspondence. A hiragana character has only one phonetic value, which represents a mora, or a syllable, in spoken Japanese. A recent positron emission tomography (PET) study [1] reported that overt reading of words written in hiragana activated bilaterally the medial and lateral occipital gyri, the posterior inferior temporal areas, Heschl’s gyri, the posterior inferior frontal areas (including Broca’s area), and the supplementary motor area. In addition, unilateral activation was seen in the left basal ganglia and the right thalamus. This PET study, however, did not reveal the temporal dynamics of the hiragana reading process. We thus attempted to follow the spatiotemporal activation sequence of cortical signals while subjects read hiragana.

Long-acting risperidone administered intramuscularly biweekly is approved for the management of schizophrenia. However, dosing of long-acting antipsychotics is frequently extended in clinical practice, and a recent clinical trial has lent support to monthly dosing of long-acting risperidone. The objective of this positron emission tomography (PET) study was to examine the striatal dopamine D(2) binding of long-acting risperidone administered intramuscularly once a month. Following at least 3 maintenance monthly injections of 50 mg long-acting risper-idone, 7 patients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder under-went PET using [(11)C]raclopride to measure D(2) binding potential within 4 days of the next scheduled injection. Data were collected from May to October 2003. This PET study was part of a larger 52-week clinical study wherein individuals received long-acting risperidone once monthly over a 1-year interval. One-year follow-up data were obtained from the 52-week parent investigation. The mean +/- SD D(2) receptor occupancy was 56% +/- 24% (range, 29%-82%). Of note, there were 4 subjects with less than 60% D(2) occupancy, none of whom relapsed over the course of the 1-year follow-up. The mean +/- SD total plasma level of risperidone plus 9-hydroxyrisperidone was 16.6 +/- 12.3 ng/mL (range, 5.7-40.8). As with plasma levels, there was considerable variability in D(2) occupancy levels for individuals receiving long-acting risperidone. This work suggests a possibility that sustained D(2) occupancy at or above the accepted threshold with acute clinical response may not be necessary to maintain response, a hypothesis with important clinical implications as we consider antipsychotic dosing and future antipsychotic development. clinicaltrials.gov Identifier: NCT00236353.

Background:Intraoperative qualitative indocyanine green (ICG) angiography has been used in cerebrovascular surgery. Hyperperfusion may lead to neurological complications after superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis. The purpose of this study is to quantitatively evaluate intraoperative cerebral perfusion using microscope-integrated dynamic ICG fluorescence analysis, and to assess whether this value predicts hyperperfusion syndrome (HPS) after STA-MCA anastomosis.Methods:Ten patients undergoing STA-MCA anastomosis due to unilateral major cerebral artery occlusive disease were included. Ten patients with normal cerebral perfusion served as controls. The ICG transit curve from six regions of interest (ROIs) on the cortex, corresponding to ROIs on positron emission tomography (PET) study, was recorded. Maximum intensity (IMAX), cerebral blood flow index (CBFi), rise time (RT), and time to peak (TTP) were evaluated.Results:RT/TTP, but not IMAX or CBFi, could differentiate between control and study subjects. RT/TTP correlated (|r| = 0.534-0.807; P < 0.01) with mean transit time (MTT)/MTT ratio in the ipsilateral to contralateral hemisphere by PET study. Bland–Altman analysis showed a wide limit of agreement between RT and MTT and between TTP and MTT. The ratio of RT before and after bypass procedures was significantly lower in patients with postoperative HPS than in patients without postoperative HPS (0.60 ± 0.032 and 0.80 ± 0.056, respectively; P = 0.017). The ratio of TTP was also significantly lower in patients with postoperative HPS than in patients without postoperative HPS (0.64 ± 0.081 and 0.85 ± 0.095, respectively; P = 0.017).Conclusions:Time-dependent intraoperative parameters from the ICG transit curve provide quantitative information regarding cerebral circulation time with quality and utility comparable to information obtained by PET. These parameters may help predict the occurrence of postoperative HPS.

Regional myocardial wall thickening assessed at rest by ECG gated 18 F-FDG positron emission tomography and by magnetic resonance imaging Positron emission tomography (PET) studies of the heart focus on...