Correction: Ankyrin-G regulates forebrain connectivity and network synchronization via interaction with GABARAP.

In the original version of this article, affiliation 3 was given as: "Division of Life Sciences, State Key Laboratory of Molecular Neuroscience, Hong Kong, University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China". This has now been corrected to: "Division of Life Sciences, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China".Additionally in the 'Data availability' section an incorrect accession code was given. The accession code has now been changed from 'PDB A9X (AnkG:GABARAPL)' to 'PDB 6A9X (AnkG:GABARAP)'.These errors have been corrected in both the PDF and HTML versions of the Article.

Ankyrin-G regulates forebrain connectivity and network synchronization via interaction with GABARAP.

GABAergic circuits are critical for the synchronization and higher order function of brain networks. Defects in this circuitry are linked to neuropsychiatric diseases, including bipolar disorder, schizophrenia, and autism. Work in cultured neurons has shown that ankyrin-G plays a key role in the regulation of GABAergic synapses on the axon initial segment and somatodendritic domain of pyramidal neurons, where it interacts directly with the GABAA receptor-associated protein (GABARAP) to stabilize cell surface GABAA receptors. Here, we generated a knock-in mouse model expressing a mutation that abolishes the ankyrin-G/GABARAP interaction (Ank3 W1989R) to understand how ankyrin-G and GABARAP regulate GABAergic circuitry in vivo. We found that Ank3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapses resulting in pyramidal cell hyperexcitability and disruptions in network synchronization. In addition, we identified changes in pyramidal cell dendritic spines and axon initial segments consistent with compensation for hyperexcitability. Finally, we identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Our results highlight the importance of ankyrin-G in regulating forebrain circuitry and provide novel insights into how ANK3 loss-of-function variants may contribute to human disease.

A single-center, prospective, double-blind, sham-controlled, randomized study of the effect of a vibrating capsule on colonic transit in patients with chronic constipation.

BACKGROUND: In an open-label study of 26 patients with IBS-C and chronic constipation, treatment with a vibrating (VIBRANT) capsule twice a week for 7.5 weeks resulted in 88.5% responders. Effects on colonic transit are unclear. We aimed to compare effects of VIBRANT and sham capsule treatment on colonic transit in patients with functional constipation. METHODS: Patients with functional constipation (Rome III criteria) were randomized to VIBRANT or sham capsule treatment for 8 weeks and underwent scintigraphic colonic transit measurements during week 8. We estimated the overall rate of colonic transit from the slope of progression of colonic geometric center over 48 hours. The capsule was activated 8 hours after ingestion, and the vibration sequence included 240 cycles. KEY RESULTS: There were no significant group differences in overall colonic transit [GC48, 2.76 (IQR 2.42-4.03) for sham group and 3.46 (2.55-4.61) for active treatment group (P=.13)]. Additionally, the progression of the isotope through the colon was numerically faster, though not significantly different (slope, P=.14) in the VIBRANT capsule group compared to the sham group. Three participants in the VIBRANT capsule group had accelerated colonic transit at 32 hours and faster colonic transit slope compared to the 95th percentile of the sham group. CONCLUSIONS AND INFERENCES: Although there were no group differences between VIBRANT and sham capsule treatment on colonic transit, at least one (and possibly three) of 12 patients receiving the VIBRANT capsule had faster colonic transit. The vibration parameters to accelerate colonic transit in patients with functional constipation require further optimization.

Opioid analgesic use among patients presenting with acute abdominal pain and factors associated with surgical diagnoses.

BACKGROUND: The prevalence of chronic opioid use among non-cancer patients presenting with acute abdominal pain (AAP) is unknown. The aim was to characterize opioid use, constipation, diagnoses, and risk factors for surgical diagnoses among non-cancer patients presenting with AAP to an emergency department (ED). METHODS: We performed a retrospective, observational cohort study of all (n=16,121) adult patients (88% from MN, IA and WI) presenting during 2014 with AAP. We used electronic medical records, and focused on 2352 adults with AAP who underwent abdominal CT scan within 24 hours of presentation. We determined odds ratios of association with constipation and features predicting conditions that may require surgery (surgical diagnosis). KEY RESULTS: There were 2352 eligible patients; 18.8% were opioid users. Constipation was more frequent in opioid (35.1%) compared to non-opioid users [OR 2.88 (95% CI 2.28, 3.62)]. Prevalence of surgical diagnosis in the opioid and non-opioid users was 35.3% and 41.7% respectively (P=.019). By univariate analysis, age and neutrophil count independently predicted increased risk, and chronic opioid use decreased risk of surgical diagnosis. Internal validation of logistic models using a randomly selected validation subset (25% of entire cohort, 587/2352) showed receiver operating characteristic (ROC) curves for the validation and full cohorts were similar. CONCLUSIONS AND INFERENCES: Approximately 19% of adults presenting with AAP were opioid users; constipation is almost three times as likely in opioid users compared to non-opioid users presenting with AAP. Factors significantly associated with altered risk of surgical diagnoses were age, opioid use, and neutrophil count.

Effects of ghrelin receptor agonist, relamorelin, on gastric motor functions and satiation in healthy volunteers.

BACKGROUND: Synthetic human ghrelin accelerates gastric emptying, reduces gastric accommodation, and results in numerical increases in postprandial symptom scores. The ghrelin receptor agonist, relamorelin, accelerates gastric emptying in patients with diabetic gastroparesis. AIM: To measure pharmacological effects of relamorelin on gastric accommodation, distal antral motility, and satiation in healthy volunteers. METHODS: In a placebo-controlled, double-blind, randomized study of 16 healthy volunteers, we compared effects of 30 µg subcutaneous (s.c.) relamorelin to placebo on: (i) gastric volumes measured by single photon emission computed tomography, (ii) 1-h postprandial distal antral motility index (MI) by 15-lumen perfusion gastroduodenal manometry, and (iii) satiation tested by Ensure nutrient drink test. Primary endpoints were: fasting and postprandial gastric volumes, distal antral phasic pressure activity (number of contractions, mean amplitude, and MI), and maximum tolerated volume. Results were normally distributed and the two treatment groups were compared using t-test. KEY RESULTS: Relamorelin, 30 µg s.c., significantly increased the number of contractions in the distal antrum during 0-60 min postmeal when compared to placebo (p = 0.022); this was also observed in the first two 15-min periods (p = 0.005 and 0.015 for number of contractions 0-15 and 16-30). There was borderline increase in MI0-15 (p = 0.055) and numerically increased MI0-60 (p = 0.139) and MI16-30 (p = 0.116). The amplitude of contractions was not significantly increased. Relamorelin did not significantly alter fasting or postprandial gastric volumes, gastric accommodation, or satiation volumes and symptoms. CONCLUSIONS & INFERENCES: Relamorelin increases frequency of distal antral motility contractions without significant effects on amplitude of contractions. The lack of inhibition of accommodation and absence of increase in satiation symptoms support relamorelin for the treatment of symptomatic gastroparesis (ClinicalTrials.gov NCT02466711).

Ehlers Danlos syndrome and gastrointestinal manifestations: a 20-year experience at Mayo Clinic.

BACKGROUND: Gastrointestinal (GI) manifestations are found in Ehlers Danlos syndrome (EDS) hypermobility subtype (HM). We aimed to assess associations between EDS HM and other EDS subtypes with GI manifestations. METHODS: We reviewed medical records of EDS patients evaluated at Mayo Clinic's Medical Genetics Clinic 1994-2013. We extracted information regarding EDS subtypes, GI manifestations, and treatments. KEY RESULTS: We identified 687 patients; 378 (56%) had associated GI manifestations (female 86.8%, diagnosis mean age 29.6 years). Of the patients identified, 58.9% (43/73) had EDS classic, 57.5% (271/471) EDS HM, 47.3% (27/57) EDS vascular subtypes. In addition, 86 patients had EDS that could not be classified in any of those three subtypes. Commonest GI symptoms were: abdominal pain (56.1%), nausea (42.3%), constipation (38.6%), heartburn (37.6%), and irritable bowel syndrome-like symptoms (27.5%). Many GI symptoms were commoner in EDS HM than the other subtypes together. Among 37.8% of the 378 patients who underwent esophagogastroduodenoscopy, the commonest abnormalities were gastritis, hiatal hernia and reflux esophagitis. Abnormal gastric emptying was observed in 22.3% (17/76): 11.8% delayed and 10.5% accelerated. Colonic transit was abnormal in 28.3% (13/46): 19.6% delayed and 8.7% accelerated. Rectal evacuation disorder was confirmed in 18/30 patients who underwent anorectal manometry. Angiography showed aneurysms in abdominal vessels in EDS vascular type. Proton pump inhibitors (38%) and drugs for constipation (23%) were the most commonly used medications. A minority underwent colectomy (2.9%) or small bowel surgery (4%). CONCLUSIONS & INFERENCES: EDS HM and other subtypes should be considered in patients with chronic functional GI symptoms and abdominal vascular lesions.

Surprises from the chromosome front: lessons from Arabidopsis on telomeres and telomerase.

Telomeres serve two vital functions: They act as a buffer against the end-replication problem, and they prevent chromosome ends from being recognized as double-strand DNA (dsDNA) breaks. These functions are orchestrated by the telomerase reverse transcriptase and a variety of telomere protein complexes. Here, we discuss our recent studies with Arabidopsis thaliana that uncovered a new and highly conserved telomere complex called CST (Cdc13/CTC1, STN1, TEN1). Formerly believed to be yeast specific, CST has now been identified as a key component of both plant and vertebrate telomeres, which is essential for genome integrity and stem cell viability. We also describe the unexpected discovery of alternative telomerase ribonucleoprotein complexes in Arabidopsis. Fueled by duplication and diversification of the telomerase RNA subunit and telomerase accessory proteins, these telomerase complexes act in concert to maintain genome stability. In addition to the canonical telomerase enzyme, one of two alternative telomerase ribonucleoprotein (RNP) complexes functions as a novel negative regulator of enzyme activity in response to genotoxic stress. These contributions highlight the immense potential of Arabidopsis in probing the depths of the chromosome end.

CD43 interaction with ezrin-radixin-moesin (ERM) proteins regulates T-cell trafficking and CD43 phosphorylation.

Cell polarization is a key feature of cell motility, driving cell migration to tissues. CD43 is an abundantly expressed molecule on the T-cell surface that shows distinct localization to the migrating T-cell uropod and the distal pole complex (DPC) opposite the immunological synapse via association with the ezrin-radixin-moesin (ERM) family of actin regulatory proteins. CD43 regulates multiple T-cell functions, including T-cell activation, proliferation, apoptosis, and migration. We recently demonstrated that CD43 regulates T-cell trafficking through a phosphorylation site at Ser-76 (S76) within its cytoplasmic tail. Using a phosphorylation-specific antibody, we now find that CD43 phosphorylation at S76 is enhanced by migration signals. We further show that CD43 phosphorylation and normal T-cell trafficking depend on CD43 association with ERM proteins. Interestingly, mutation of S76 to mimic phosphorylation enhances T-cell migration and CD43 movement to the DPC while blocking ERM association, showing that CD43 movement can occur in the absence of ERM binding. We also find that protein kinase CΘ can phosphorylate CD43. These results show that while CD43 binding to ERM proteins is crucial for S76 phosphorylation, CD43 movement and regulation of T-cell migration can occur through an ERM-independent, phosphorylation-dependent mechanism.

The effect of scatter and attenuation on aerosol deposition as determined by gamma scintigraphy.

Gamma scintigraphy is often used to quantify deposition patterns from aerosol inhalers. The errors caused by scatter and tissue attenuation in planar Tc-99m gamma scintigraphy were investigated based on the data collected from four subjects in this study. Several error correction methods were tested. The results from two scatter correction methods, Jaszczak's method and factor analysis of dynamic sequences (FADS), were similar. Scatter accounted for 20% of raw data in the whole lung, 20% in the oropharynx, and 43% in the central airways and esophagus. Three attenuation correction methods were investigated and compared. These were: uniform attenuation correction (UAC), a known method used for inhalation drug imaging work; the broad-beam attenuation correction used for organ imaging in nuclear medicine; and a narrow-beam inhomogeneous tissue attenuation correction proposed in this study. The three methods differed significantly (p < 0.05), but all indicated that attenuation is a severe quantification problem. The narrow beam attenuation correction with scatter correction, showed that raw data underestimated tracer deposition by 44% in the lung, 137% in the oropharynx, and 153% in the trachea/esophageal region. To quantify aerosol lung deposition using planar scintigraphy even in relative terms, corrections are necessary. Much of the literature concerning quantified aerosol dose distributions measured by gamma scintigraphy needs to be interpreted carefully.

Iterative optimal design of PET experiments for estimating beta-adrenergic receptor concentration.

To estimate in vivo myocardial beta-adrenergic receptor concentration with sufficient precision and to reduce the experimental complexities in positron emission tomography (PET), an iterative optimal design method is applied. An initial three-injection protocol, utilising [F-18]-labelled (R)- and (S)-fluorocarazolol and unlabelled (S)-fluorocarazolol, is optimised for ligand dosages and administration times to maximise the precision of all model parameters using the D-optimal criterion. Using this experimental protocol, PET data are collected in porcine studies, and model parameters are estimated. All model parameters are identified with satisfactory precision. The in vivo myocardial beta-receptor concentration is 7.5+/-0.6 pmol x ml(-1), which corresponds to the in vitro result of 10.1+/-1.3 pmol x ml(-1). With more accurate parameter values, a simplified two-injection protocol is optimally designed, utilising only radiolabelled and unlabelled (S)-fluorocarazolol, based on a new criterion to maximise the precision of the beta-receptor concentration. This revised optimum design predicts that the in vivo beta-receptor concentration can be estimated with good precision but reduced experiment complexity.

Polyploid evolution and biogeography in Chelone (Scrophulariaceae): morphological and isozyme evidence.

Chelone is a genus of perennial herbs comprising three diploid species (C. cuthbertii, C. glabra, and C. lyonii) and a fourth species (C. obliqua) that occurs as tetraploid and hexaploid races. To assess patterns of isozyme and morphological variation, and to test hypotheses of hybridization and allopolyploidy, we analyzed variation among 16 isozyme loci from 61 populations and 16 morphological characters from 33 populations representing all taxa and ploidy levels. Based on morphological analyses using clustering (unweighted pair group method using an arithmetic average) and ordination (principal components analysis and canonical variance analysis) methods, we recognize three diploid species without infraspecific taxa. Polyploids in the C. obliqua complex were most similar morphologically to diploid populations of C. glabra and C. lyonii. Patterns of isozyme variation among polyploids, which included fixed heterozygosity and recombinant profiles of alleles present in diploids, suggested polytopic origins of tetraploids and hexaploids. Our data indicate independent origins of polyploids in or near the southern Blue Ridge, Interior Highlands and Plains, and Atlantic Coastal Plain regions from progenitors most similar to C. glabra and C. lyonii. Extant tetraploids were not implicated in evolution of hexaploids, and plants similar to C. cuthbertii appeared unlikely as diploid progenitors for polyploids. We propose multiple differentiation and hybridization/polyploidization cycles in different geographic regions to explain the pattern of allopatry and inferred polytopic origins among polyploids.

Simultaneous recovery of size and radioactivity concentration of small spheroids with PET data.

UNLABELLED: Quantification of tumor activity is used to predict prognosis and discriminate benign from malignant lesions identified by PET. Accurate quantitation of small lesions requires correction for the partial volume effects. Such a correction is often based on the recovery coefficient (RC), which depends on the lesion size, the object-to-background ratio (OBR) and physical properties of the media. The purpose of this investigation was to determine whether a model-based optimization method to simultaneously recover the size and the activity concentration of small spheroids could improve estimates of lesion radioactivity when object size is unknown. For reference, we compared our method with a widely used approach, RC correction, that requires the object size to be known. METHODS: A three-dimensional, spatially varying, object size- and contrast-dependent Gaussian model of the point spread function (PSF) of an ECAT EXACT was developed. The observed dependence of the PSF on random coincidences and measured-peak/background activity were included in the PSF using three adjusting factors. Size and radioactivity concentration of a spheroid were estimated by adjusting size and concentration until model output best matched the image data. Elliptic and circular phantoms both containing seven hot spheroids, with OBRs ranging from 5.6 to 0 background, were evaluated. RESULTS: The proposed quantification method reduced the activity error by 11%-63% of the error obtained without correction. The greatest error reduction occurred for small spheroids. The average error in radius estimation ranged from 2% to 48%, wherein the smallest spheroid produced the largest errors. For spheroids with diameters from 8 to 22 mm, Student t test (paired, one-tail) showed the proposed method significantly improved accuracy (P < 0.05) in comparison with the RC method and also in comparison with optimization without the three adjusting factors. CONCLUSION: The model-based optimization method improved estimation of radioactivity concentration over that corrected by the RC method and that made without any correction. It also provided accurate estimation of size for spheroids larger than 6 mm in diameter.

PET quantification of specific binding of carbon-11-nicotine in human brain.

UNLABELLED: Previous work on the PET measured uptake of (S)-[11C]nicotine presents conflicting findings as to whether it reflects specific binding. METHODS: We studied the uptake of (R)-[11C]nicotine and (S)-[11C]nicotine in normal volunteers at baseline conditions and after a challenge with unlabeled (S)-nicotine to decrease the concentration of free binding sites or with CO2 to increase perfusion. We analyzed the data using two- and three-compartment models. RESULTS: We found tissue pharmacokinetics of (R)- and (S)-[11C]nicotine are adequately described by the two-compartment model. (S)-nicotine challenge induced small but statistically significant reductions in distribution volume (DV) of both (R)- and (S)-[11C]nicotine. The changes in DV could not be attributed to perfusion changes because DV was not affected by CO2 challenge. Although the reduction in DV indicates sensitivity of [11C]nicotine to status of nicotinic binding sites, the small magnitude of the reduction suggests that most nicotine uptake is nonspecific. CONCLUSION: Although differences in DV attributable to specific binding were detected, (R)- and (S)-[11C]nicotine are relatively poor tracers for studying nicotinic binding sites using PET.

A method to correct for scatter, spillover, and partial volume effects in region of interest analysis in PET.

Scatter and spatial resolution effects degrade the accuracy of radioactivity concentration estimates obtained from positron emission tomography (PET) data. We present and evaluate a methodology for region quantification which accounts for these degradations. The method is based on analysis of sinogram data and does not require dynamic data sequences to be reconstructed. Moreover, estimates of region variance are also produced which may be used to define weights for model analyses that use weighted least squares minimization in order to obtain unbiased parameter estimates. We evaluate the method using both simulation and measured data and find that, with an appropriate model of scatter and spatial resolution effects, it is unbiased and capable of quantifying myocardial concentration with no more than a 5% error in accuracy for myocardium as thin as 10 mm.

A nonlinear spatially variant object-dependent system model for prediction of partial volume effects and scatter in PET.

Accurate quantitation of small lesions with positron emission tomography (PET) requires correction for the partial volume effect. Traditional methods that use Gaussian models of the PET system were found to be insufficient. A new approach that models the non-Gaussian object-dependent scatter was developed. The model consists of eight simple functions with a total of 24 parameters. Images of line and disk sources in circular and elliptical cylinders, and an anthropomorphic chest phantom were used to determine the parameter values. Empirical rules to determine these parameter values for various objects based on those for a reference object, a 21.5-cm circular cylinder, were also proposed. For seven spheroids and a 3.4-cm cylinder, pixel values predicted by the model were compared with the measured values. The model-to-measurement-ratio was 1.03+/-0.07 near the center of the spheroids and 0.99+/-0.03 near the center of the 3.4-cm cylinder. In comparison, the standard single Gaussian model had corresponding ratios of 1.27+/-0.09 and 1.24+/-0.03, respectively, and the corresponding ratios for a double Gaussian model were 1.13+/-0.09 and 1.05+/-0.01. Scatter fraction (28.5%) for a line source in the 21.5-cm cylinder was correctly estimated by our model. Because of scatter, we found that errors in the measurement of activity in spheroids with diameters from 0.6 to 3.4 cm were more significant than previously appreciated.

Global cerebral blood flow, blood volume, and oxygen metabolism in patients with migraine headache.

OBJECTIVE: Migraine headaches with and without aura are representative of vascular headache states traditionally thought to be mediated by alterations in vascular tone. Validation of this theory has been hampered in part by technical difficulties inherent in the measurement of cerebral blood flow (CBF). The purpose of this study was to compare CBF measured during migraine and migraine-free states using PET. METHODS: Patients with a minimum of one migraine headache without aura per month (International Headache Society [IHS] criteria) underwent measurement of CBF, cerebral blood volume (CBV), oxygen extraction, and metabolism during an episode of spontaneous migraine headache. Imaging was repeated during a migraine-free period of at least 48 hours. PET radiotracers used were: CBF, H(2)15O; CBV, C15O; oxygen metabolism, 15O2. RESULTS: In nine patients (seven female and two male), global CBF (mL/min/100 g [SD]) was measured as 52.70 (6.9) during migraine and 59.65 (10.6) in the migraine-free state; p=0.028. CBV (mL/100 g [SD]) was 3.6 (0.43) during the symptomatic state and 3.8 (0.55) after the migraine; p=0.047. Oxygen metabolism (mL/min/100 g [SD]) was 3.68 (0.9) during migraine and 3.38 (1.02) without headache; p=0.211. The oxygen extraction ratio was 0.48 (0.15) and 0.41 (0.12) during migraine and migraine-free states, respectively; p=0.132. CONCLUSIONS: In patients experiencing migraine without aura, CBF and CBV are reduced during the headache phase. Cerebral oxygen metabolism and oxygen extraction are not significantly affected.

A robust edge detection method for gated radionuclide ventriculograms.

UNLABELLED: We present a myocardial edge detection technique that was developed for fast, reproducible measurements of left ventricular ejection fraction in the clinical setting. METHODS: This myocardial edge detection method compares three edge parameters--count amplitude and first and second count derivatives--in three consecutive locations along a radius to a predetermined template of these values. Each of the radii, defined at 10-degree intervals, has different template values that permit accurate edge detection even though adjacent structures, such as the left atrium and the right ventricle, alter edge parameters. The template for edge detection is based on either the average edge parameters determined from manually defined edges in 15 patients (automatic method) or an operator-defined edge in the first frame (semiautomatic method). RESULTS: The edge detection methods were tested in 100 patients, and intraobserver variabilities as well as comparison with clinically obtained ejection fractions were calculated. The standard error of the estimate was less than 3.1% for all observer comparisons. In 15 patients with both high-count (400,000 counts per image) and low count (50,000 counts per image) studies, the mean absolute difference in ejection fraction was 2.6% for intraobserver comparisons. CONCLUSION: A robust myocardial edge detection technique was developed that is applicable for routine clinical use.

Optimal experiment design for PET quantification of receptor concentration.

The mathematical models used to analyze positron emission tomography (PET) data obtained for receptor quantitation have many unknown parameters which must be estimated from the data. Obtaining unique and precise estimates of the model parameters from PET data is difficult as a result of the complex interdependence of the parameters. Here the authors address the task of estimating the concentration of myocardial beta-adrenergic receptors using unlabeled and (18)F-labeled S(-)-fluorocarazolol as the receptor ligand. For a three-injection study the authors have optimized the ligand injection times and dosages using the D-optimal criterion for estimating receptor concentration. They found that in optimizing a three-injection experimental design, the dose of ligand in the third injection approaches zero so that the optimal three-injection design is actually a two-injection experiment. Using this optimal experiment, the authors demonstrate estimates of receptor concentration that are almost five times as precise as compared to an empirically designed three-injection experiment.

Specific beta-adrenergic receptor binding of carazolol measured with PET.

UNLABELLED: Carazolol is a promising high-affinity beta-adrenergic receptor ligand for the noninvasive determination of beta receptor status using PET. Earlier investigations demonstrated specific receptor binding of carazolol in mice. These PET studies with S(-)-[2"-11C]carazolol in pigs were performed to explore the utility of the tracer for PET receptor studies. METHODS: Tracer uptake in the heart and lung was measured by PET as a function of time. Receptors were blocked with propranolol and different doses of ICI 118,551 to estimate specific binding. Fluorine-18-1"-Fluorocarazolol and the less active R-enantiomer of [11C]-carazolol were also studied. RESULTS: Specific receptor binding was 75% of the total uptake in the heart, preventable and displaceable by propranolol. Dose-dependent competition showed that carazolol binds in vivo to beta 1 and to beta 2 subtypes. Uptake of the labeled R(+) enantiomer of carazolol was not receptor-specific. CONCLUSIONS: Carazolol labeled with 11C or 18F is a strong candidate for use in receptor estimation with PET. The in vivo observations were consistent with its known high affinity and slow receptor dissociation rate. Its high specific receptor uptake and low metabolism allow existing kinetic models to be applied for receptor measurements. The 11C label is convenient for repeated administrations, though 18F allowed the long observation periods necessary for measurement of the receptor dissociation rate. If needed, nonspecific uptake can be estimated without pharmacologic intervention by using the labeled R enantiomer.