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Neuroimaging, particularly that of neuroreceptor radioisotope and functional magnetic resonance imaging (fMRI), has played a fundamental role in neuropharmacology and neurophysiology. Because of the unique and pioneering role, especially of the radiolabeling of central nervous system (CNS) drugs for receptor and neurotransmitter system imaging, there is an increasingly major role to aid in CNS drug development. One component is providing evidence for proof of concept of the target for which candidate drugs are being tested for receptor occupancy mechanism of action and ultimately rational drug dosing. There is also a role for other areas of neuroimaging, including fMRI and magnetic resonance spectroscopy in other magnetic resonance-based techniques that, together with radioisotope imaging, represent 'CNS molecular imaging.' The role of these approaches and a review of the recent advances in such neuroimaging for proof-of-concept studies is the subject for this paper. Moreover, hypothetical examples and possible algorithms for early discovery/phase I development using neuroimaging provide specific working approaches. In summary, this article reviews the vital biomarker approach of neuroimaging in proof of concept studies.

The widely used Logan plot in radioligand receptor dynamic PET studies produces marked noise-induced negative biases in the estimates of total distribution volume (DV(T)) and binding potential (BP). To avoid the inconsistencies in the estimates from the Logan plot, a new graphical analysis method was proposed and characterized in this study. The new plot with plasma input and with reference tissue input was first derived to estimate DV(T) and BP. A condition was provided to ensure that the estimate from the new plot equals DV(T) or BP. It was demonstrated theoretically that 1) the statistical expectations of the estimates from the new plot with given input are independent of the noise of the target tissue concentration measured by PET; and 2) the estimates from the time activity curves of regions of interest are identical to those from the parametric images for the new plot. The theoretical results of the new plot were also confirmed by computer simulations and fifty-five human [(11)C]raclopride dynamic PET studies. By contrast, the marked noise-induced underestimation in the DV(T) and BP images and noise-induced negative bias in the estimates from the Logan plot were demonstrated by the same data sets used for the new plot. The computational time for generating DV(T) or BP images in the human studies was reduced by 80% on average by the new plot in contrast to the Logan plot. In conclusion, the new plot is a consistent and computationally efficient graphical analysis method to improve the quantification of reversible tracer binding in radioligand receptor dynamic PET studies.

In high-resolution emission tomography imaging, even small patient movements can considerably degrade image quality. The aim of this work was to develop a general approach to motion-corrected reconstruction of motion-contaminated data in the case of rigid motion (particularly brain imaging) which would be applicable to any PET scanner in the field, without specialized data-acquisition requirements.Assuming the ability to externally track subject motion during scanning (e.g., using the Polaris camera), we proposed to incorporate the measured rigid motion information into the system matrix of the expectation maximization reconstruction algorithm. Furthermore, we noted and developed a framework to incorporate the additional effect of motion on modifying the attenuation factors. A new mathematical brain phantom was developed and used along with elaborate combined Simset/GATE simulations to compare the proposed framework with the cases of no motion correction.Clear qualitative and quantitative improvements were observed when incorporating the proposed framework. The method is very practical to implement for any scanner in the field, not requiring any hardware modifications or access to the list-mode acquisition capability.

In recent years, there has been substantial progress in studying the dopamine transporter, a unique component of the functioning dopaminergic nerve terminal. The transporter has been studied by direct binding techniques using a variety of ligands which function as inhibitors of transport. Analogues of these ligands have been used as photoaffinity labels to solubilize and further characterize the transporter. While a variety of drugs bind to the transporter, it is clear that the transporter may serve as an important drug receptor, particularly for the reinforcing properties of some psychostimulants such as cocaine. An extension of the in vitro ligand-binding studies reveals that it is possible to preferentially label the transporter in vivo. The success of in vivo labeling has lead to successful positron emission tomographic scanning studies of the transporter. These studies in turn have revealed the usefulness of imaging the transporter, a measure of the presence of dopaminergic nerve terminals, as a potential diagnostic tool in Parkinson's disease.

Background: Studies in abstinent methamphetamine (METH) users have demonstrated reductions in brain dopamine transporter (DAT) binding potential (BP), as well as cognitive and motor deficits, but it is not yet clear whether cognitive deficits and brain DAT reductions fully reverse with sustained abstinence, or whether behavioral deficits in METH users are related to dopamine (DA) deficits. This study was conducted to further investigate potential persistent psychomotor deficits secondary to METH abuse, and their relationship to brain DAT availability, as measured using quantitative PET methods with [11C]WIN 35428. Methods: Twenty-two abstinent METH users and 17 healthy non-METH using controls underwent psychometric testing to test the hypothesis that METH users would demonstrate selective deficits in neuropsychiatric domains known to involve DA neurons (e.g., working memory, executive function, motor function). A subset of subjects also underwent PET scanning with [11C]WIN 35428. Results: METH users were found to have modest deficits in short-term memory, executive function, and manual dexterity. Exploratory correlational analyses revealed that deficits in memory, but not those in executive or motor function, were associated with decreases in striatal DAT BP. Conclusions: These results suggest a possible relationship between DAT BP and memory deficits in abstinent METH users, and lend support to the notion that METH produces lasting effects on central DA neurons in humans. As METH can also produce toxic effects on serotonin (5-HT) neurons, further study is needed to address the potential role of brain 5-HT depletion in cognitive deficits in abstinent METH users. Synapse 62:91–100, 2008. © 2007 Wiley-Liss, Inc.

Udgivelsesdato: 2008-May Tourette syndrome (TS) is a neuropsychiatric disorder with childhood onset characterized by motor and phonic tics. Obsessive-compulsive disorder (OCD) is often concomitant with TS. Dysfunctional tonic and phasic dopamine (DA) and serotonin (5-HT) metabolism may play a role in the pathophysiology of TS. We simultaneously measured the density, affinity, and brain distribution of dopamine D(2) receptors (D(2)-R's), dopamine transporter binding potential (BP), and amphetamine-induced dopamine release (DA(rel)) in 14 adults with TS and 10 normal adult controls. We also measured the brain distribution and BP of serotonin 5-HT(2A) receptors (5-HT(2A)R), and serotonin transporter (SERT) BP, in 11 subjects with TS and 10 normal control subjects. As compared with controls, DA(rel) was significantly increased in the ventral striatum among subjects with TS. Adults with TS+OCD exhibited a significant D(2)-R increase in left ventral striatum. SERT BP in midbrain and caudate/putamen was significantly increased in adults with TS (TS+OCD and TS-OCD). In three subjects with TS+OCD, in whom D(2)-R, 5-HT(2A)R, and SERT were measured within a 12-month period, there was a weakly significant elevation of DA(rel) and 5-HT(2A) BP, when compared with TS-OCD subjects and normal controls. The current study confirms, with a larger sample size and higher resolution PET scanning, our earlier report that elevated DA(rel) is a primary defect in TS. The finding of decreased SERT BP, and the possible elevation in 5-HT(2A)R in individuals with TS who had increased DA(rel), suggest a condition of increased phasic DA(rel) modulated by low 5-HT in concomitant OCD.Neuropsychopharmacology (2008) 33, 1239-1251; doi:10.1038/sj.npp.1301528; published online 7 November 2007.

The development of the radioligands for PET imaging of the cerebral cannabinoid receptor (CB1) is of great importance for studying its role in neuropsychiatric disorders, obesity, and drug dependence. None of the currently available radioligands for CB1 are suitable for quantitative PET, primarily because of their insufficient binding potential (BP) in brain or low penetration through the blood-brain barrier (BBB). The goal of this study was to evaluate 11C-JHU75528, an analog of the selective CB1 antagonist rimonabant, in vivo as a potential CB1 radioligand for PET.The brain regional distribution and pharmacology of 11C-JHU75528 have been evaluated in vivo in mice (dissection) and baboons (PET).11C-JHU75528 readily entered the mouse and baboon brain and specifically and selectively labeled cerebral CB1 receptors. The ratio of striatum to brain stem in mice and the binding potential (BP) in the baboon putamen were 3.4 and 1.3-1.5, respectively. The specific binding of 11C-JHU75528 in vivo was blocked by preinjection of nonlabeled JHU75528. Administration of rimonabant (1 mg/kg, intravenously) also blocked the specific binding of 11C-JHU75528 in the mouse and baboon brain, whereas various central noncannabinoid drugs did not significantly reduce the 11C-JHU75528 binding in the mouse brain. 11C-JHU75528 formed several hydrophilic metabolites, but only a minute fraction of metabolic radioactivity penetrated the BBB.11C-JHU75528 holds promise as a radiotracer with suitable imaging properties for quantification of CB1 receptors in the human brain.

We tested the hypothesis that movement abnormalities induced by chronic manganese (Mn) exposure are mediated by dysfunction of the nigrostriatal dopamine system in the non-human primate striatum. Motor function and general activity of animals was monitored in parallel with chronic exposure to Mn and Positron Emission Tomography (PET) studies of in vivo dopamine release, dopamine transporters and dopamine receptors in the striatum. Analysis of metal concentrations in whole blood and brain was obtained and post-mortem analysis of brain tissue was used to confirm the in vivo PET findings. Chronic Mn exposure resulted in subtle motor function deficits that were associated with a marked decrease of in vivo dopamine release in the absence of a change in markers of dopamine (DA) terminal integrity or dopamine receptors in the striatum. These alterations in nigrostriatal DA system function were observed at blood Mn concentrations within the upper range of environmental, medical and occupational exposures in humans. These findings show that Mn-exposed non-human primates that exhibit subtle motor function deficits have an apparently intact but dysfunctional nigrostriatal DA system and provide a novel mechanism of Mn effects on the dopaminergic system.

Although it is well established that acute benzodiazepine administration impairs episodic memory encoding, little is known about the neuroanatomical substrates of this effect.The objective was to examine the acute dose effects of the benzodiazepine hypnotic triazolam on brain activity during episodic memory encoding.After oral capsule administration (placebo, 0.1, 0.2, and 0.4 mg/70 kg triazolam), regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) with 15O-H2O during performance of semantic categorization and orthographic categorization tasks in a double-blind, within-subject design in 12 healthy volunteers. The rCBF associated with episodic memory encoding was measured by subtracting the rCBF during orthographic categorization from that during semantic categorization and by examining correlations between brain activity during encoding and subsequent recognition memory performance.Results in the placebo condition replicated those of nonpharmacological encoding studies, including activation in left ventrolateral prefrontal cortex. Correlations between brain activity and subsequent memory performance additionally showed medial temporal activation. Triazolam produced dose-related impairment in memory performance and dose-related deactivation in encoding-associated areas including right prefrontal cortex, left parahippocampal gyrus, and left anterior cingulate cortex.Results are consistent with behavioral evidence that benzodiazepines impair prefrontal control processes as well as contextual memory and episodic binding processes thought to be controlled by the medial temporal lobe. In addition to elucidating the brain mechanisms underlying these benzodiazepine-induced behavioral deficits, results of this study also help validate hypotheses generated in nonpharmacological neuroimaging studies regarding the processes controlled by these brain regions.

In high resolution emission tomography imaging, even small patient movements can considerably degrade image quality. This work investigates an approach to motion compensated reconstruction of motion-contaminated data, thus applicable to any scanner in the field (e.g. without list-mode acquisition capability), assuming externally-tracked motion information; it involves incorporation of the measured motion information into the system matrix of the EM algorithm. Furthermore, it is shown that the effect of motion-contamination of the attenuation factors should also be modeled and taken into account in the reconstruction task.

We describe a computer system designed to meet the data processing needs of a high-volume brain PET research center based on the High Resolution Research Tomograph (HRRT). Listmode data are collected by an acquisition computer and stored on a high-speed disk. A workflow management program transfers the data through a gigabit network, rebins events into sinograms, and calculates correction factors. Reconstruction jobs are performed on a 64 processor cluster. We developed methods for dynamically allocating subclusters from the pool of available nodes, and reconstructing multiple images on multiple subclusters simultaneously. We also studied overall workflow. In our initial plan, scatter and randoms calculation unexpectedly became a bottleneck. We therefore adjusted our plan so that scatter estimation was performed initially in low resolution, and later expanded to high resolution.

Udgivelsesdato: 2006-Dec In all, 19 research subjects, with current histories of frequent cocaine use, were exposed to cocaine-related cues to elicit drug craving. We measured the change of occupancy of dopamine at D2-like receptors with positron emission tomography (PET) and inferred a change of intrasynaptic dopamine (endogenous dopamine release), based on the displacement of radiotracer [(11)C]raclopride. Receptor occupancy by dopamine increased significantly in putamen of participants who reported cue-elicited craving compared to those who did not. Further, the intensity of craving was positively correlated with the increase in dopamine receptor occupancy in the putamen. These results provide direct evidence that occupancy of dopamine receptors in human dorsal striatum increased in proportion to subjective craving, presumably because of increased release of intrasynaptic dopamine.

Background Sex differences in addictive disorders have been described. Preclinical studies have implicated the striatal dopamine system in these differences, but human studies have yet to substantiate these findings. Methods Using positron emission tomography (PET) scans with high-specific-activity [ 11 C] raclopride and a reference tissue approach, we compared baseline striatal dopamine binding potential (BP) and dopamine release in men and women following amphetamine and placebo challenges. Subjective drug effects and plasma cortisol and growth hormone responses were also examined. Results Although there was no sex difference in baseline BP, men had markedly greater dopamine release than women in the ventral striatum. Secondary analyses indicated that men also had greater dopamine release in three of four additional striatal regions. Paralleling the PET findings, men's ratings of the positive effects of amphetamine were greater than women's. We found no sex difference in neuroendocrine hormone responses. Conclusions We report for the first time a sex difference in dopamine release in humans. The robust dopamine release in men could account for increased vulnerability to stimulant use disorders and methamphetamine toxicity. Our findings indicate that future studies should control for sex and may have implications for the interpretation of sex differences in other illnesses involving the striatum.

Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D2/D3 dopamine receptors in human striatum. Here, the occupancy of D2/D3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [18F]fallypride PET scan. Receptor occupancy was calculated as percent reduction in binding potential relative to unblocked values measured in seven normal volunteers. Mean D2/D3 receptor occupancy was statistically significantly higher in cortical (inferior temporal cortex 55%) than in striatal regions (putamen 36%, caudate 43%, p

Glial cell activation occurs in response to brain injury and is present in a wide variety of inflammatory processes including dementia associated with human immunodeficiency virus (HIV). HIV-infected glial cells release cytokines and chemokines that, along with viral neurotoxins, contribute to neuronal damage and apoptosis. The purpose of this study was to determine if glial cell activation in HIV-positive (HIV+) patients could be detected noninvasively, in vivo, using [11C]-R-PK11195 with positron emission tomography (PET). [11C]-R-PK11195 is a selective radioligand for the peripheral benzodiazepine receptor (PBR), and is known to reflect the extent of glial cell activation. A subaim was to determine if nondemented HIV+ patients could be distinguished from those with HIV-associated dementia (HAD) on the basis of [11C]-R-PK11195 binding. Five healthy volunteers and 10 HIV+ patients underwent PET with [11C]-R-PK11195. Time-radioactivity curves (TACs) were generated from dynamic PET images in nine regions of interest (ROIs) drawn on coregistered magnetic resonance imaging (MRI) scans. The average radioactivity was calculated in each ROI and was normalized to the average radioactivity in white matter. Patients with HAD showed significantly higher [11C]-R-PK11195 binding than controls in five out of eight brain regions (P < .05, Mann-Whitney U test). Nondemented HIV+ patients did not show significantly increased binding compared to controls. HIV+ patients overall (demented and nondemented) showed significantly higher radioligand binding than controls in five brain regions (P < 0.05). Patients with HAD did not show significant differences in binding when compared to HIV+ nondemented patients. The findings of this pilot study support a role for glial cell activation in HAD, and that PET with [11C]-R-PK11195 can detect the concomitants of neuronal damage in individuals infected with HIV.

To improve the reliability and sensitivity of quantitative analysis in the study and evaluation of brain tumor using Ga-68 EDTA dynamic PET, a linear parametric imaging algorithm was developed in this study for estimation of both distribution volume (DV) and blood brain barrier permeability. F statistics was used for separating tumor from normal tissue. A two-compartmental model was used to describe the tracer kinetics. The operational equations: C/sub pet/=((K/sub 1/+k/sub 2/)V/sub p/)/spl int/C/sub p/ds-k/sub 2//spl int/C/sub pet/ds+V/sub p/C/sub p/ and /spl int/C/sub pet/=(DV+V/sub p/)/spl int/C/sub p/ds-(1/k/sub 2/)C/sub pet/+(V/sub p//k/sub 2/)C/sub p/, were used to estimate K/sub 1/ (permeability) and DV(=K/sub 1//k/sub 2/), respectively. A reliable and robust linear regression with spatial constraint parametric imaging algorithm was developed to generate the K/sub 1/ and DV images. Pixel-wise F statistics with 2 and k-2 degree of freedom was calculated as: F=(((k-2)k/(2(k/sup 2/-1)))D/sup 2/ with D/sup 2/=(x-/spl mu/)'S/sup -1/(x-/spl mu/), where the sample is from two dimensional sample space {(K/sub 1/, DV)} of reference regions in normal brain tissue pixels, the sample size k is the number of pixels within the normal reference ROIs, /spl mu/ and S are, respectively, the sample mean vector (K/sub 1/, DV) and covariance matrix. By setting critical a values at 0.2, 0.05, and 0.001, statistical significance level images were generated, and its pixel values can be, 0 if F 0.92) was found between the values of K/sub 1/ and DV estimated by model fitting to ROI time activity curve and ones calculated from parametric images. The method for generating K/sub 1/, DV, F, and significance level images is of high computation efficiency and is easy to be implemented. The statistical model developed in the current study provided a tool to integrate the multi-dimensional physiological information. The normal reference region method and the integration of multi-physiological images may improve the sensitivity and specificity of brain tumor detection and evaluation of treatment.

(11)C-Raclopride has been widely used for PET studies of dopamine D(2/3) receptors in human brain. The long half-life of (18)F may impart advantages to the novel moderate-affinity benzamide (18)F-desmethoxyfallypride and its high-affinity congener (18)F-fallypride for competition studies and for detection of extrastriatal binding. However, the in vivo kinetics of these compounds and the quantification approaches for parametric mapping of their specific bindings have not been systematically compared.Dynamic emission recordings of the 3 tracers were obtained in groups of healthy subjects. A conventional model, graphical analysis using metabolite-corrected arterial inputs, and models with reference tissue inputs were used to calculate voxelwise parametric maps of the equilibrium distribution volume (V(d)) and the binding potential (BP) of the 3 radioligands in brain. To test for bias, voxelwise kinetic results were compared with those obtained by volume-of-interest (VOI) analysis.The V(d) and BP estimates obtained by VOI analysis did not differ from the mean of voxelwise estimates in the same striatal volumes. In striatum, the mean (18)F-desmethoxyfallypride BP ranged from 1.9 to 2.5, whereas the mean (11)C-raclopride BP ranged from 3 to 4, depending on the method used for calculation. In contrast, the mean BP of (18)F-fallypride ranged from 16 to 27 in striatum and could also be readily quantified in the thalamus.Reference tissue methods for the voxelwise calculation of binding parameters are suitable for parametric mapping of the 3 dopamine D(2/3) receptor ligands.

(+)-Amphetamine, (+/-)-ephedrine, and phentermine are commonly used appetite suppressants that release monoamines from nerve cells by acting as substrates for biogenic amine transporters. One key difference among the three drugs is their selectivity for norepinephrine (NE) release vs. dopamine (DA) release. The NE/DA selectivity ratios for these drugs as determined in vitro [(EC50 NE(-1))/(EC50 DA(-1))] are (+/-)-ephedrine (18.6) > phentermine (6.7) > (+)-amphetamine (3.5). The in vitro data suggest that when administered in vivo, these stimulants might differ in their ability to release DA from nerve terminals in the brain. To test this hypothesis, noradrenergic effects (i.e., plasma NE) and dopaminergic effects (i.e., central DA release) were assessed when each drug was administered intravenously (1.5 mg/kg) to anesthetized baboons. Central DA release was determined via positron emission tomography using the method of [11C]raclopride displacement. In the present investigation, high doses of these stimulants increased plasma NE and DA in parallel, but only (+)-amphetamine released central DA from neurons and decreased plasma prolactin. None of the drugs altered plasma amine metabolite levels, indicating no inhibition of monoamine oxidase activity at the administered doses. Plasma drug levels measured in baboons were higher than those measured in human patients taking prescribed doses of the drugs. Viewed collectively, the present data indicate that typical clinical doses of phentermine and (+/-)-ephedrine may not release central DA in humans, a hypothesis that should ultimately be tested in controlled clinical studies.

There is evidence that stress and glucocorticoids alter drug self-administration and mesolimbic dopamine (DA) activity in preclinical models. The primary purpose of this study was to test the hypothesis that glucocorticoids are associated with psychostimulant reinforcement and DA release in humans. In total, 16 healthy adults, ages 18–27 years, underwent two consecutive 90-min PET studies with high specific activity [11C]raclopride. The first scan was preceded by intravenous saline, and the second by intravenous amphetamine (AMPH 0.3 mg/kg). DA release was defined as the percent change in raclopride binding between the placebo and AMPH scans. Measures of subjective drug effects, plasma cortisol, and growth hormone (GH) were obtained. Findings showed that cortisol levels were positively associated with AMPH-induced DA release in the left ventral striatum (LVS) and the dorsal putamen. Subjects with higher cortisol responses to AMPH also reported more positive subjective drug effects than subjects with lower cortisol responses; no association was observed between cortisol levels and negative drug effects. Higher ratings of positive drug effects were also associated with greater DA release in the LVS, dorsal putamen, and dorsal caudate. A general lack of relationship was observed between GH responses to AMPH and DA release or subjective drug responses. Our findings provide evidence of interrelationships between glucocorticoid levels, subjective responses to IV AMPH, and brain DA release in humans. The results are consistent with those of preclinical studies, suggesting that individual differences in HPA axis function may influence vulnerability to alcohol and drug dependence in humans.

Publisher Summary This chapter summarizes some of the important maps of neuroreceptors that have been at work over the last 20 years. Positron-emitting radioligands and radiolabeled substrates of transmitter synthesizing enzymes were created for the in vivo imaging of brain tissue with positron emission tomography (PET). This class of tracers has advanced the search for mechanisms that regulate neurotransmission in the living human brain, but the methods of image analysis and interpretation are still controversial. The chapter discusses the main problems affecting the interpretations of the impressive maps of neuroreceptors including: (1) the discrepant meanings of the various measures called binding potential by different practitioners, (2) the uncertain definition of the Michaelis half-saturation constant and its consequent sensitivity to external influences, (3) the sensitivity of the steady-state measures of binding potential, maximum receptor number, and Michaelis half-saturation constant to the absence of a fully established steady state, and (4) the various interpretations of binding potential change reported by different practitioners of neuroreceptor mapping. The chapter also presents a number of solutions by the analysis of these issues and problems.

Several studies suggest that cognitive tasks attenuate activation of the limbic system by emotional stimuli. We investigated the possibility that worry would similarly inhibit the limbic system by examining its effects on regional cerebral blood flow (rCBF). Ten nonanxious volunteers underwent four scans within one session, using positron emission tomography (PET) with H(2)(15)O as tracer. The first two scans recorded emotionally neutral thinking induced after listening to tapes describing neutral statements. Preceding the third and fourth scans, subjects listened to the self-recorded tape describing their individual worries, were instructed to continue to worry, and were scanned 5 min later. Subjects rated themselves as more anxious during the worry scans but showed no significant heart interbeat or skin conductance changes. During worry, rCBF increases were found bilaterally in the medial fronto-orbital gyri and the right thalamus; rCBF decreases were found bilaterally in the hippocampi and amygdalae, in the right insula, the left and right inferior, middle and superior temporal gyri and the occipito-temporal gyri, the right inferior occipital gyrus and the left supramarginal gyrus. Activity of the left orbito-frontal gyrus was negatively correlated with activity of the amygdalae. The results support the hypothesis that worry-induced prefrontal activity suppresses affect-related subcortical regions.

In vivo imaging of the central nervous system (CNS) neuroreceptors in humans began was used in the early 1980s. Now, some twenty years later, the success of radiopharmaceutical imaging is still often one based on empiricism and serendipity. Nevertheless, a number of factors can be identified based on the robot experience in developing these radiotracers. This article will describe some of the issues that may be useful in choosing approaches to radiolabel ligands as future imaging agents of neuroreceptors, transporters and intrasynaptic measures of neurotransmitters. A description of the current process from hypothesis to radiochemical preclinical development, non-human primate imaging development of quantitative procedures finally leading to toxicology, dosimetry and eventually human applications are provided. The role of important factors including metabolism and lipophilicity, affinity and other factors for optimizing radiolabeling strategies is dealt with. Furthermore, issues involving decision making of how far to extend efforts in developing a radiotracer and when might be an appropriate stopping place are discussed. Finally some typical examples of the use of these radiotracers, especially with emphasis on stable drug design and development, are provided. These include occupancy studies and mechanism of action studies. In summary, the prediction of tracer success includes: first, identification of appropriate targets and precursors, then systematic optimization of ligands with continuous feedback from pharmacokinetics and iterative improvement based on unsuccessful tracers. This article is intended to present a pragmatic overview of the radiopharmaceutical development process with emphasis on the CNS.

There has been substantial progress in the imaging of dopamine transporters. The earliest positron emission tomography (PET) experiments used carbon-11 labeled nominfensine (1,44); whereas recent investigations by both PET and single photon emission computed tomography (SPECT) utilize a variety of ligands with a variety of properties and address many biological questions (see below). The earliest ligands utilized, [11C]nomifensine and [11C]cocaine, were somewhat limited because of low signal-to-noise ratios. Nevertheless, [11C]cocaine as a ligand continues to be popular, because it is the same authentic substance that is abused around the world. The best, current 3-substituted phenyltropane ligands, such as RTI-55, have vastly improved signal-to-noise ratios. These successes are in no small part because of the development of the chemistry of cocaine analogs and other analogs of inhibitors for transporters (Fig. 1) (4,8). Despite this progress, several important things remain to be achieved. We need to develop methods to carry out rigorous calculations of Bmax instead of relying on more inexact but easier measures of relative occupancy and binding potential. We also need useful ligands for all transporters in brain.

Little is known about serotonin neurons in Parkinson disease (PD).To study the serotonin system in PD with positron emission tomography, using the serotonin transporter radioligand [11C](+)McN5652.We measured the density of the serotonin transporter and the density of [11C]WIN35,428-labeled dopamine transporters in the striatum of 13 adults with PD and 13 age- and sex-matched controls. To assess the effects of possible differences in blood flow or brain atrophy, we also measured regional cerebral blood flow and the size of the regions of interest for the caudate nucleus and putamen.Patients with PD showed reductions in the specific distribution volumes of [11C](+)McN5652 in the caudate (P.01) and putamen (P.01), along with the expected reductions in striatal [11C]WIN35,428 binding (P.01). There were no reductions in regional cerebral blood flow or the sizes of the regions of interest, mitigating against potential confounding effects of blood flow, brain atrophy, or partial volume effects. Reductions in serotonin transporter binding correlated with ratings of disease staging.These results suggest that the density of serotonin transporters, like that of dopamine transporters, is reduced in the striatum of patients with PD and that these changes are related to disease stage.

Antihistamines are effective medications that have been used for decades in the management of allergic rhinitis; however, they may be administered or selected in an inappropriate fashion and may be the source of drug-related morbidity. Our objective is to present relevant background information and an expert consensus statement on the use of antihistamines in treatment of allergic rhinitis. In July 2002, 14 experts in allergy, clinical immunology, pharmacology, and impairment assessment were invited to participate in a roundtable conference to present current concepts and develop a consensus statement on the clinical management of allergic rhinitis with antihistamines. Many of the antihistamines used to treat allergic rhinitis, as well as the disease itself, may produce sedation, impairment, and reduced quality of life. Allergic rhinitis is more appropriately managed with the relatively nonimpairing second-generation antihistamines (eg, loratadine, desloratadine, cetirizine, and fexofenadine), because older agents (eg, diphenhydramine, chlorpheniramine, and brompheniramine) produce sedation and impairment and worsen sleep architecture. Although there is some debate surrounding the varying degrees of efficacy of second-generation antihistamines, it is known that some agents may produce varying levels of drowsiness or impairment, especially at higher than recommended doses. The differences with regard to safety among the second-generation antihistamines are smaller than are the differences between the first and second generations. A nonsedating, nonimpairing (even at higher than recommended doses), second-generation antihistamine is preferred for all patients, particularly those with a higher risk for the development of adverse effects. We recommend that primary care and specialist physicians, nurse practitioners, physician assistants, pharmacists, and all other health professionals involved in the diagnosis and treatment of allergic rhinitis follow this consensus document and share this information with patients for whom antihistamine therapy is recommended. In addition, further epidemiologic studies on the effects of antihistamines should be performed.

For the quantitative analysis of ligand-receptor dynamic positron emission tomography (PET) studies, it is often desirable to apply reference tissue methods that eliminate the need for arterial blood sampling. A common technique is to apply a simplified reference tissue model (SRTM). Applications of this method are generally based on an analytical solution of the SRTM equation with parameters estimated by nonlinear regression. In this study, we derive, based on the same assumptions used to derive the SRTM, a new set of operational equations of integral form with parameters directly estimated by conventional weighted linear regression (WLR). In addition, a linear regression with spatial constraint (LRSC) algorithm is developed for parametric imaging to reduce the effects of high noise levels in pixel time activity curves that are typical of PET dynamic data. For comparison, conventional weighted nonlinear regression with the Marquardt algorithm (WNLRM) and nonlinear ridge regression with spatial constraint (NLRRSC) were also implemented using the nonlinear analytical solution of the SRTM equation. In contrast to the other three methods, LRSC reduces the percent root mean square error of the estimated parameters, especially at higher noise levels. For estimation of binding potential (BP), WLR and LRSC show similar variance even at high noise levels, but LRSC yields a smaller bias. Results from human studies demonstrate that LRSC produces high-quality parametric images. The variance of R(1) and k(2) images generated by WLR, WNLRM, and NLRRSC can be decreased 30%-60% by using LRSC. The quality of the BP images generated by WLR and LRSC is visually comparable, and the variance of BP images generated by WNLRM can be reduced 10%-40% by WLR or LRSC. The BP estimates obtained using WLR are 3%-5% lower than those estimated by LRSC. We conclude that the new linear equations yield a reliable, computationally efficient, and robust LRSC algorithm to generate parametric images of ligand-receptor dynamic PET studies.

Nicotine is self-administered by smoking tobacco products, and enhances positive mood (at least in smokers). Since most drugs of abuse decrease regional cerebral metabolic rate(s) for glucose (rCMRglc) in human subjects, we posited that administration of nicotine would similarly reduce rCMRglc. Positron emission tomography (PET) with [F-18]fluorodeoxyglucose was used to assess the effects of intravenous nicotine (1.5 mg) on cerebral glucose metabolism in six healthy male volunteers (21-38 years of age). Two PET assays (placebo and nicotine) were performed, and subjective self-reports of mood and feeling state were collected. Data were analyzed using analysis of variance. Nicotine reduced global glucose metabolism (by 9.51% of placebo control), with reductions in most of the 30 individual regions tested. Nine regions had bilateral effects that reached statistical significance (p&

Substituted benzamides such as (11)C-raclopride or (123)I-iodobenzamide are selective radiotracers for PET and SPECT imaging of D(2)-like dopamine (DA) receptors. (18)F-Desmethoxyfallypride ((18)F-DMFP) is a benzamide tracer with the advantage of an (18)F label. We optimized the synthesis and evaluated (18)F-DMFP in PET studies on healthy human volunteers.The affinity of DMFP for D(2)-like DA receptors was characterized in vitro using membrane preparations from rat striatum and the DA receptor ligand (3)H-spiperone. PET studies on 10 healthy human volunteers were performed using a whole-body PET scanner after injection of 214 +/- 54 MBq (mean +/- SD) (18)F-DMFP. Brain images were acquired dynamically over 124 min, and metabolite-corrected plasma activity was used as the input function. Data analysis was performed using several different approaches (compartmental, graphical, equilibrium methods).The mean inhibition constant (K(i)) of DMFP was 15 +/- 9 nmol/L. In human brain, the striatum-to-cerebellum ratio reached a maximum of about 4 between 60 and 120 min. When specific binding in the striatum was expressed as the difference between binding in the striatum and the cerebellum, it reached a maximum at approximately 60 min after injection and remained almost constant until the end of data acquisition. The ratio of specific striatal to nonspecific cerebellar binding was about 3:1 at 120 min after injection. A small, but significant specific tracer binding could also be detected in the thalamus. Treatment of a schizophrenic patient with a high dose (1,000 mg/d) of another substituted benzamide, amisulpride, resulted in a reduction of specific tracer uptake of about 90% in striatal regions. With regard to measured distribution volumes and binding potentials, there was an excellent agreement between all applied analytic methods.Our study demonstrates that (18)F-DMFP is a highly reliable tracer for PET imaging of D(2)-like DA receptors. It offers the major advantage that it can be used independently of an on-site cyclotron within a PET satellite network. Noninvasive analytic methods without blood sampling provide valid measurements of receptor quantities in human striatum. Because of the (18)F label and the favorable imaging properties, (18)F-DMFP could become an efficient substitute for (11)C-raclopride in a clinical context.

Objective: Dopaminergic abnormalities in frontal-subcortical circuits have been hypothesized as the underlying pathophysiologic mechanism in Tourette’s syndrome. The objective of this study was to test the hypothesis that presynaptic dopamine release from the striatum is abnormal in adults with Tourette’s syndrome. Method: Seven adults with Tourette’s syndrome and five age-matched comparison subjects each received two positron emission tomography (PET) scans with high specific activity [ 11 C]raclopride. The first scan followed an intravenous injection of saline; the second followed an intravenous injection of amphetamine. The relative dopamine release was estimated as the percentage difference in binding potential between the postsaline and postamphetamine scans. Results: Binding potential determined after the initial [ 11 C]raclopride scan did not significantly differ between Tourette’s syndrome and comparison subjects. After amphetamine challenge, the mean value of intrasynaptic dopamine in the putamen (as determined by true equilibrium bolus estimation) increased by 21% in the subjects with Tourette’s syndrome and did not change in the comparison subjects; the mean values increased by 16.9% and decreased by 1.8%, respectively, when measured by the constrained method. Dopamine release in the caudate region was not significantly different in the Tourette’s syndrome and comparison subjects. Conclusions: Greater putamen dopamine release was seen in adults with Tourette’s syndrome than in comparison subjects after a pharmacologic challenge with amphetamine. These results suggest that the underlying pathobiology in Tourette’s syndrome is a phasic dysfunction of dopamine transmission.

According to the ternary complex model of G-protein linkage to receptors, agonists increase the affinity of the receptors for the G protein. The model predicts that an endogenous agonist's constant of inhibition toward an agonist radioligand is lower than that toward an antagonistic radioligand. The authors hypothesized that competition from endogenous dopamine in striatum of living mice should have a greater effect on the binding of the D2,3partial agonist N-[3H]propylnorapomorphine than on the binding of the D2,3antagonist [11C]raclopride. The baseline binding potential ( pB(0)), defined as the ratio of bound-to-unbound ligand in the absence of competition from endogenous dopamine, was simultaneously measured in mouse striatum for [11C]raclopride ( pB(0)= 8.5) and N-[3H]propylnorapomorphine ( p′B(0) = 5.3). The baseline was established by treatment with α-methyl- p-tyrosine and reserpine. Relative to these baseline values in saline-treated mice, the pBof N-[3H]propylnorapomorphine decreased 52% whereas the pBof [11C]raclopride decreased only 30%, indicating greater sensitivity of the former compound to inhibition by synaptic dopamine. Furthermore, amphetamine decreased the pBof N-[3H]propylnorapomorphine to a greater extent (73%) than that of [11C]raclopride (43%) relative to the reserpine condition. For both radioligands, the occupancy of the dopamine receptors by endogenous agonist obeyed Michaelis-Menten kinetics over a wide range of agonist concentrations established by the pharmacologic treatments. The apparent inhibition constant of endogenous dopamine depended on the dopamine occupancy and decreased to a value 1.66 times greater for N-[3H]propylnorapomorphine than for [11C]raclopride at its highest occupancies. The results are consistent with the hypothesis that agonist binding is more sensitive than antagonist binding to competition from endogenous dopamine. Therefore, dopamine agonist ligands may be superior to benzamide antagonist ligands for the estimation of dopamine receptor occupancy by endogenous synaptic dopamine. The analysis of the effect of dopamine occupancy on the inhibition of N-[3H]propylnorapomorphine binding indicated a limited supply of G protein with a maximum ternary complex fraction of 40% of maximum agonist binding capacity.

The purpose of this study was to examine the metabolic basis for magnetic resonance (MR) spectroscopic imaging findings in focal brain lesions of patients with acquired immunodeficiency syndrome (AIDS).The authors combined MR spectroscopic imaging with [11C-methyl]thymidine positron emission tomography (PET) and thallium-201 single photon emission computed tomography (SPECT) in 10 patients. They sought a characteristic metabolite profile that would enable differentiation of benign lesions from primary central nervous system lymphoma and determined whether PET and SPECT results supported the MR spectroscopic imaging findings.Metabolite compositions of the lesions were similar, likely because the lesions were late stage and tended to be necrotic. Brain lesions in patients with AIDS were nonspecific regarding metabolic profile as determined with MR spectroscopic imaging. All patients with positive PET and SPECT studies had primary central nervous system lymphoma.PET and SPECT may be more reliable than MR spectroscopic imaging for differentiating benign lesions from primary central nervous system lymphoma in patients with AIDS.

Imaging of glutamate carboxypeptidase II (GCP II), also known as N -acetylated α-linked l -amino dipeptidase (NAALADase), may enable study of glutamatergic transmission, prostate cancer, and tumor neovasculature in vivo. Our goal was to develop a probe for GCP II for use with positron emission tomography (PET). Radiosynthesis of 11 C–MeCys–C(O)–Glu or 11 C-( S )-2-[3-(( R )-1-carboxy-2-methylsulfanyl-ethyl)-ureido]-pentanedioic acid ( 11 C-MCG), an asymmetric urea and potent ( K i = 1.9 nM) inhibitor of GCP II, was performed by C-11 methylation of the free thiol. Biodistribution of 11 C-MCG was assayed in mice, and quantitative PET was performed in a baboon. 11 C-MCG was obtained in 16% radiochemical yield at the end of synthesis with specific radioactivities over 167 GBq/mmol (4000 Ci/mmol) within 30 min after the end of bombardment. At 30 min postinjection, 11 C-MCG showed 33.0 ± 5.1%, 0.4 ± 0.1%, and 1.1 ± 0.2% ID/g in mouse kidney (target tissue), muscle, and blood, respectively. Little radioactivity gained access to the brain. Blockade with unlabeled MCG or 2-(phosphonomethyl)pentanedioic acid (PMPA), another potent inhibitor of GCP II, provided sevenfold and threefold reductions, respectively, in binding to target tissue. For PET, distribution volumes (DVs) were 1.38 then 0.87 pre- and postblocker (PMPA). Little metabolism of 11 C-MCG occurred in the mouse or baboon. These results suggest that 11 C-MCG may be useful for imaging GCP II in the periphery.

The value of parametric images that represent both spatial distribution and quantification of the physiological parameters of tracer kinetics has long been recognized. However, the inherent high noise level of pixel kinetics of dynamic PET makes it unsuitable to generate parametric images of the microparameters of tracer kinetic model by conventional weighted nonlinear least squares (WNLS) fitting. Based on the concept that both spatial and temporal information should be integrated to improve parametric image quality, a nonlinear ridge regression with spatial constraint (NLRRSC) parametric imaging algorithm was proposed in this study. For NLRRSC, a term that penalizes local spatial variation of parameters was added to the cost function of WNLS fitting. The initial estimates and spatial constraint were estimated by component representation model (CRM) with cluster analysis. A hierarchical cluster with average linkage method was used to extract components. The ridge parameter was determined by linear ridge regression theory at each iteration, and a modified Gauss‐Newton algorithm was used for minimizing the cost function. Results from a computer simulation showed that the percent mean square error of estimates obtained by NLRRSC can be decreased by 60 ‐ 80% compared to that of WNLS. The parametric images estimated by NLRRSC are significantly better than the ones generated by WNLS. A highly correlated linear relationship was found between the ROI values calculated from the microparametric images generated by NLRRSC and estimates from ROI kinetic fitting. NLRRSC provided a reliable estimate of glucose metabolite uptake rate with a comparable image quality compared to Patlak analysis. In conclusion, NLRRSC is a reliable and robust parametric imaging algorithm for dynamic PET studies. © 2002 Elsevier Science (USA)

Erratum to “Memory decline shows stronger associations with estimated spatial patterns of amyloid deposition progression than total amyloid burden” [Neurobiol. Aging 34 (2013) 2835e2842] Rachel A. Yotter *, Jimit Doshi , Vanessa Clark , Jitka Sojkova , Yun Zhou , Dean F. Wong , Luigi Ferrucci , Susan M. Resnick , Christos Davatzikos a Center for Biomedical Image Computing and Analytics, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA b Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD 21224, USA Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD d Longitudinal Studies Section, National Institute on Aging, Baltimore, MD

To quantify changes in neuronal nAChR binding in vivo, quantitative dynamic SPECT studies were performed with 5-[ 123 I]-iodo-A-85380 in baboons pre and post chronic treatment with (-)-nicotine or saline control. Infusion of (-)-nicotine at a dose of 2.0 mg/kg/24h for 14 days resulted in plasma (-)-nicotine levels of 27.3 ng/mL. This is equivalent to that found in an average human smoker (20 cigarettes a day). In the baboon brain the regional distribution of 5-[ 123 I]-iodo-A-85380 was consistent with the known densities of nAChRs (thalamus > frontal cortex > cerebellum). Changes in nAChR binding were estimated from the volume of distribution ( V d ) and binding potential ( BP ) derived from 3-compartment model fits. In the (-)-nicotine treated animal V d was significantly increased in the thalamus (52%) and cerebellum (50%) seven days post cessation of (-)-nicotine treatment, suggesting upregulation of nAChRs. The observed 33% increase in the frontal cortex failed to reach significance. A significant increase in BP was seen in the thalamus. In the saline control animal no changes were observed in V d or BP under any experimental conditions. In this preliminary study, we have demonstrated for the first time in vivo upregulation of neuronal nAChR binding following chronic (-)-nicotine treatment.

Objective: In acute cardiac rejection, changes in myocardial oxygen consumption occur; non-invasive detection of these metabolic changes would have obvious clinical utility. In the classic cervical, heterotopic, canine, transplant model, the heart is non-working. It has a low myocardial oxygen consumption. Creation of a working model with normal myocardial oxygen consumption would enhance validity of non-human studies. Methods: Clearance of 11 C acetate was determined by positron emission tomography (PET) scanning and compared with myocardial oxygen consumption in normal and transplanted canine hearts. Donor hearts from mongrel dogs (2.5‐3 kg; na 4) were transplanted into the neck of adult beagles (12‐15 kg; na 4), no immunosuppression was given. Two non-working hearts were modified to eject only coronary flow via the right ventricle. In two hearts, a novel working model was created with aortic regurgitation to load the left ventricle. Working and non-working hearts underwent PET scanning on post-operative days 2 and 4. Normal dog hearts (na 2) and native hearts of transplanted dogs (na 3) were used to validate the scanning technique. Coronary sinus and aortic oxygen saturation data along with myocardial blood flow (radiolabeled microspheres) confirmed that clearance of 11 C acetate in normal and transplanted hearts followed a biexponential model. Results: Myocardial oxygen consumption was correlated with the rate constant of 11 C acetate rapid phase clearance (ra 0:91) in normal and transplanted hearts. The working hearts had increased myocardial oxygen consumption compared to non-working hearts. Conclusions: This study (1) introduces a model of a working heterotopic cardiac transplantation with near-normal oxygen consumption; and (2) demonstrates that regional myocardial oxygen consumption in transplanted hearts can be detected by 11 C acetate PET. q 2001

Udgivelsesdato: 2000-Oct The ligands N-methylspiperone and haloperidol both bind to D(2)-like dopamine receptors. The competitive nature of the binding over a wide range of haloperidol concentrations and the effect on dopamine release have never been tested in vivo. We determined the competitive interaction between 3-N-[(11)C]methylspiperone ([(11)C]NMSP) and haloperidol binding to striatal dopamine D(2)-like receptors with positron emission tomography (PET) of pig brain. [(11)C]NMSP tomography was performed with haloperidol at five different plasma concentrations maintained constant by programmed infusion. Kinetic parameters of ligand competition for binding in the striatum were determined by deconvolving time-activity curves of the striatum and cerebellum from metabolite-corrected arterial plasma [(11)C]NMSP and haloperidol concentrations. Two types of [(11)C]NMSP-binding sites were evident in the striatum, both saturable by haloperidol administration. The preponderant or primary sites bound [(11)C]NMSP irreversibly, as dopamine D2-like receptors, while the secondary sites bound [(11)C]NMSP reversibly, as do serotonin S2 receptors. Woolf-Hanes plots revealed the predicted approximately linear relationships between the binding indices and the haloperidol plasma concentration. For the irreversible binding sites, this relationship indicated a 50% inhibitory concentration of haloperidol of 2 nM in plasma and a maximum binding capacity of 64 pmol cm(-3) in striatum. For the reversible binding sites, the relationship indicated a 50% inhibitory plasma concentration of haloperidol of 1 nM and a maximum binding capacity of 4.5 pmol cm(-3). Second-order polynomial Eadie-Hofstee-Scatchard plots were consistent with increased competition from an endogenous ligand of the irreversibly binding sites only with increasing doses of haloperidol. At the highest haloperidol dose, this hypothetical endogenous ligand had risen 6-7-fold. We contend that this reveals the release of dopamine by high concentrations of haloperidol.

Antipsychotic drug development has been a slow process since the discovery of chlorpromazine more than 45 years ago. Researchers identify a large number of potential compounds; screen them for antipsychotic activity in in vitro and animal test models; devise appropriate formulations; perform preclinical pharmacology, pharmacokinetic, and toxicology studies; perform healthy volunteer and then patient clinical studies; and finally negotiate with regulatory agencies for drug approval. In the United States, this process takes an average of 10 to 12 years and costs more than $500 million per approved drug. More recently, the pharmaceutical industry is benefiting from a new wave of technologic innovations that have advanced our understanding of the biology of disease processes and increased the efficiency of the research and development process. However, while these new technologies may appear to be expensive, by providing the basis for early go/no-go decisions, technologies such as PET can actually be cost-effective. To ensure that innovative drug research continues, a practical strategy (rational drug design) to evaluate drugs more efficiently in terms of both time and cost (fewer studies with fewer patients) must be developed for each new drug candidate. One of the most important and difficult steps in the drug development process is defining the dose-response relationship. Using M100907 as an example, we demonstrated that mechanism-based research promotes cost-effective drug development. The therapeutic index of M100907 was defined in phase I single- and multiple-dose tolerability studies. Nuclear imaging using PET technology was then used to confirm the mechanism of action of M100907 in the target organ (living human brain) and to target an appropriate dose range and regimen. With these data, clear go/no-go decision points could be established early within the clinical drug development process, and the selection of M100907 doses to carry forward into large-scale clinical trials in patients with schizophrenia could be narrowed.

A radiosynthetic method to prepare the nicotinic acetylcholine receptor radioligand (S)-5-[123I]iodo-3-(2-azetidinylmethoxy)pyridine, 5-IA, has been developed. The two-step sequence produced [123I]-5-IA in high radiochemical yield (52%), high radiochemical purity (98%), and high specific radioactivities (> 8,500 mCi/mumol). Preliminary single photon emission computed tomography studies with [123I]-5-IA in baboon demonstrated the appropriate regional localization for a high-affinity nicotinic radioprobe (thalamus > frontal cortex > cerebellum). Pretreatment with cytisine blocked [123I]-5-IA uptake in all brain regions (78-59% reduction), demonstrating the specificity of the radiotracer.

The relation between striatal dopamine D2 receptor binding and aging was investigated in rhesus monkeys with PET. Monkeys (n = 18, 39 to 360 months of age) were scanned with 11C-raclopride; binding potential in the striatum was estimated graphically. Because our magnetic resonance imaging analysis revealed a concomitant relation between size of striatum and age, the dynamic positron emission tomography (PET) data were corrected for possible partial volume (PV) artifacts before parameter estimation. The age-related decline in binding potential was 1% per year and was smaller than the apparent effect if the age-related change in size was ignored. This is the first in vivo demonstration of a decline in dopamine receptor binding in nonhuman primates. The rate of decline in binding potential is consistent with in vitro findings in monkeys but smaller than what has been measured previously in humans using PET. Previous PET studies in humans, however, have not corrected for PV error, although a decline in striatal size with age has been demonstrated. The results of this study suggest that PV correction must be applied to PET data to accurately detect small changes in receptor binding that may occur in parallel with structural changes in the brain.

The increasing public health impact of addictive disorders and obesity has led to an emphasis on studying the neurobiology of reward. Studies of reward integrate basic and cognitive neuroscience with in vivo approaches in humans. In this issue of PNAS, Dreher et al. (1) use neuroimaging to visualize the in vivo neurochemistry and neural circuitry of reward in older and younger adults. They show different relationships (1) between estimated dopa decarboxylase activity (DDC), assessed through PET measurement of the presynaptic dopamine (DA) system with [18F]flurodopa (FDopa), a radiolabeled derivative of dopa (measure of DA), and reward measured by fMRI networks. They found that midbrain measures of FDopa correlated positively with the BOLD signal after tasks eliciting a reward mechanism in youth but negatively in aged subjects. There were also regional differences in brain activation between the two age groups.