NEW HAVEN, CT, United States

Molecular Neuroimaging, Llc
NEW HAVEN, CT, United States
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Samanez-Larkin G.R.,Vanderbilt University | Buckholtz J.W.,Harvard University | Cowan R.L.,Vanderbilt University | Woodward N.D.,Vanderbilt University | And 8 more authors.
Biological Psychiatry | Year: 2013

Background: Everyday life demands continuous flexibility in thought and behavior. We examined whether individual differences in dopamine function are related to variability in the effects of amphetamine on one aspect of flexibility: task switching. Methods: Forty healthy human participants performed a task-switching paradigm following placebo and oral amphetamine administration. [18F]fallypride was used to measure D2/D3 baseline receptor availability and amphetamine-stimulated dopamine release. Results: The majority of the participants showed amphetamine-induced benefits through reductions in switch costs. However, such benefits were variable. Individuals with higher baseline thalamic and cortical receptor availability and striatal dopamine release showed greater reductions in switch costs following amphetamine than individuals with lower levels. The relationship between dopamine receptors and stimulant-enhanced flexibility was partially mediated by striatal dopamine release. Conclusions: These data indicate that the impact of the psychostimulant on cognitive flexibility is influenced by the status of dopamine within a thalamocorticostriatal network. Beyond demonstrating a link between this dopaminergic network and the enhancement in task switching, these neural measures accounted for unique variance in predicting the psychostimulant-induced cognitive enhancement. These results suggest that there may be measurable aspects of variability in the dopamine system that predispose certain individuals to benefit from and hence use psychostimulants for cognitive enhancement. © 2013 Society of Biological Psychiatry.

PubMed | Molecular Neuroimaging, Llc, Southwestern University, University of North Texas, University of Texas at Dallas and Avid Radiopharmaceuticals
Type: | Journal: Psychiatry research | Year: 2016

Compulsive tanning despite awareness of ultraviolet radiation (UVR) carcinogenicity may represent an addictive behavior. Many addictive disorders are associated with alterations in dopamine (D2/D3) receptor binding and dopamine reactivity in the brains reward pathway. To determine if compulsive tanners exhibited neurobiologic responses similar to other addictive disorders, this study assessed basal striatal D2/D3 binding and UVR-induced striatal dopamine efflux in ten addicted and ten infrequent tanners. In a double-blind crossover trial, UVR or sham UVR was administered in separate sessions during brain imaging with single photon emission computerized tomography (SPECT). Basal D2/D3 receptor density and UVR-induced dopamine efflux in the caudate were assessed using (123)I-iodobenzamide ((123)I-IBZM) binding potential non-displaceable (BPnd). Basal BPnd did not significantly differ between addicted and infrequent tanners. Whereas neither UVR nor sham UVR induced significant changes in bilateral caudate BPnd in either group, post-hoc analyses revealed left caudate BPnd significantly decreased (reflecting increased dopamine efflux) in the addicted tanners - but not the infrequent tanners - during the UVR session only. Bilateral BPnd correlated with tanning severity only in the addicted tanners. These preliminary findings are consistent with a stronger neural rewarding response to UVR in addicted tanners, supporting a cutaneous-neural connection driving excessive sunbed use.

PubMed | Molecular Neuroimaging, Llc, Butler Hospital and Avid Radiopharmaceuticals
Type: | Journal: Brain : a journal of neurology | Year: 2017

The advent of tau-targeted positron emission tomography tracers such as flortaucipir (

Barthel H.,University of Leipzig | Gertz H.-J.,University of Leipzig | Dresel S.,Helios Hospital Berlin Buch | Peters O.,Charité - Medical University of Berlin | And 7 more authors.
The Lancet Neurology | Year: 2011

Background: Imaging with amyloid-β PET can potentially aid the early and accurate diagnosis of Alzheimer's disease. Florbetaben ( 18F) is a promising 18F-labelled amyloid-β-targeted PET tracer in clinical development. We aimed to assess the sensitivity and specificity of florbetaben ( 18F) PET in discriminating between patients with probable Alzheimer's disease and elderly healthy controls. Methods: We did a multicentre, open-label, non-randomised phase 2 study in 18 centres in Australia, Germany, Switzerland, and the USA. Imaging with florbetaben ( 18F) PET was done on patients with probable Alzheimer's disease (age 55 years or older, mini-mental state examination [MMSE] score=18-26, clinical dementia rating [CDR]=0·5-2·0) and age-matched healthy controls (MMSE ≥28, CDR=0). Our primary objective was to establish the diagnostic efficacy of the scans in differentiating between patients with probable disease and age-matched healthy controls on the basis of neocortical tracer uptake pattern 90-110 min post-injection. PET images were assessed visually by three readers masked to the clinical diagnosis and all other clinical findings, and quantitatively by use of pre-established brain volumes of interest to obtain standard uptake value ratios (SUVRs), taking the cerebellar cortex as the reference region. This study is registered with, number NCT00750282. Findings: 81 participants with probable Alzheimer's disease and 69 healthy controls were assessed. Independent visual assessment of the PET scans showed a sensitivity of 80% (95% CI 71-89) and a specificity of 91% (84-98) for discriminating participants with Alzheimer's disease from healthy controls. The SUVRs in all neocortical grey-matter regions in participants with Alzheimer's disease were significantly higher (p<0·0001) compared with the healthy controls, with the posterior cingulate being the best discriminator. Linear discriminant analysis of regional SUVRs yielded a sensitivity of 85% and a specificity of 91%. Regional SUVRs also correlated well with scores of cognitive impairment such as the MMSE and the word-list memory and word-list recall scores (r -0·27 to -0·33, p≤0·021). APOE e{open}4 was more common in participants with positive PET images compared with those with negative scans (65% vs 22% [p=0·027] in patients with Alzheimer's disease; 50% vs 16% [p=0·074] in healthy controls). No safety concerns were noted. Interpretation: We provide verification of the efficacy, safety, and biological relevance of florbetaben ( 18F) amyloid-β PET and suggest its potential as a visual adjunct in the diagnostic algorithm of dementia. Funding: Bayer Schering Pharma AG. © 2011 Elsevier Ltd.

Seiby J.,Institute for Neurodegenerative Disorders | Seiby J.,Molecular Neuroimaging, Llc | Seiby J.,Yale University | Russell D.,Institute for Neurodegenerative Disorders | And 6 more authors.
Seminars in Nuclear Medicine | Year: 2012

Brain imaging of striatal dopamine terminal degeneration serves an important role in the clinical management of Parkinson's disease (PD). Imaging biomarkers for interrogating dopaminergic systems are used for clarifying diagnosis when only subtle motor symptoms are present. However, motor dysfunction is not the earliest symptom of PD. There is increasing interest in identifying premotor PD patients, particularly because potential disease-modifying therapies are developed and the clinical imperative becomes early and accurate diagnosis. On the other end of the spectrum of the disease course, during later stages of PD, significant clinical challenges like levo-dopa-induced dyskinesias and medication on-off phenomenon become more prevalent. In this instance, better understanding of altered PD motor pathways suggests the potential utility of novel treatments targeting neuronal systems that are impacted by degenerating dopamine neurons and chronic dopamine replacement treatment. Molecular neuroimaging serves unique roles in both very early PD and later-stage disease, in the former, potentially pushing back the time of diagnosis, and in the latter, elucidating pathology relevant to new drug development. © 2012 Elsevier Inc.

Seibyl J.,Molecular Neuroimaging, Llc | Seibyl J.,Yale University | Russell D.,Molecular Neuroimaging, Llc | Russell D.,Yale University | And 3 more authors.
Quarterly Journal of Nuclear Medicine and Molecular Imaging | Year: 2012

The central role of dopamine neuronal loss in Parkinson's disease provides a clear pathologic framework and rationale for imaging the system both to interrogate dynamic pathophysiologic changes as well as to aid in diagnosis and clinical management. Recent post mortem studies of Parkinson's brain provide a much fuller depiction of the inexorable and progressive topology of pathophysiologic changes, including brain alpha-synuclein deposition. This informs PET and SPECT evaluations for testing hypotheses regarding the course of degeneration in longitudinal studies of Parkinson's disease patients. Recent work has underscored the subtlety of change in the dopaminergic neuronal system and its neural connections as a function of disease status and treatment. The interplay between other neurochemical brain systems and dopamine elucidates potential new targets for therapeutic intervention across the stages of the disease.

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase II | Award Amount: 2.41M | Year: 2012

DESCRIPTION (provided by applicant): We propose to develop a software package to automatically evaluate a subject's beta amyloid PET scan (using either C11-PIB, F18-florbetaben, or F18-florbetapir, F18-flutemetamol) by normalizing the subject's scan, masking away non-gray matter tissue (without relying on co-registered MRI scans), placing standardized ROIs onto the transverse slices, and reporting SUVr values in separate brain areas referenced to the cerebellar gray matter. Our goal is that this analysis package ultimately would be FDA-510(k) approved and distributed to hospitals and clinics (and pharmaceutical companies), as a commercial product, to aid in the evaluation and diagnosis of patients. Through the use of such a validated and standardized analysis package, new radio-tracers can be objectively compared for their accuracy in quantitating beta amyloid in the brain, and more importantly, new therapies can be objectively and quantitatively evaluated for their efficacy in preventing or removing beta amyloid for each patient, on a personalized individual basis. An important portion of the testing, user interface evaluation, and ADER's report generation utility and clinical application will be conducted in a subaward under the supervision of Dr. Michael Devous within the Nuclear Medicine Center at the UT Southwestern Medical Center, Dallas, Texas. At MNI, New Haven, we will continue to test and evaluate ADER in house within our Radio-tracer Evaluation Program (RTEP) program, where we continue to test potential new beta amyloid PET and SPECT imaging agents, while clinically evaluating subjects by our in-house neurologists and support staff. The potential benefit to society is considerable since an ADER analysis package would provide a quantitative biomarker analysis method for Alzheimer's disease progression for individualized therapy efficacy. Alzheimer's disease (AD) is associated with significant morbidity and a useful marker and/or brain scan analysis package, like this proposed ADER, would add to our understanding of AD disease progression and provide objective assessment of neuroprotective and restorative therapies. This fully automated image processing will also allow for fewer subjects to be studied (with the same clinical power) in clinical trials using new PET and SPECT radioligands. As new tracers and therapies are developed, ADER would co-evolve with these studies into an optimized image analysis method for diagnosing, staging and treating Alzheimer's disease. PUBLIC HEALTH RELEVANCE: Evaluation of Radiotracers (ADER) Project Narrative We propose to develop an automated package for analysis of beta-amyloid accumulation in Alzheimer's patients' brains which can be easily implemented by pharmaceutical companies for therapeutic drug discovery, aswell as in a clinical setting, for high quality quantitative PET (and SPECT) imaging assessments. This analysis will remove subjectivity in the determination of the imaging outcome measure and permit a reproducible evaluation of new Alzheimer's radio- tracers' imaging potential. ADER can be used to test the efficacy of new Alzheimer's therapies in which FDA Phase II tested radiotracers are used as surrogate biomarkers. Our validated image processing package is highly relevant to the ongoing search for new diagnostics and treatments since it will serve as a new medical device (as defined by the FDA), which will improve the way in which medical care is delivered to Alzheimer's patients.

PubMed | Molecular Neuroimaging, Llc
Type: Journal Article | Journal: Journal of labelled compounds & radiopharmaceuticals | Year: 2016

Phosphodiesterase (PDE) 4 is the most prevalent PDE in the central nervous system (CNS) and catalyzes hydrolysis of intracellular cAMP, a secondary messenger. By therapeutic inhibition of PDE4, intracellular cAMP levels can be stabilized, and the symptoms of psychiatric and neurodegenerative disorders including depression, memory loss and Parkinsons disease can be ameliorated. Radiotracers targeting PDE4 can be used to study PDE4 density and function, and evaluate new PDE4 therapeutics, in vivo in a non-invasive way, as has been shown using the carbon-11 labeled PDE4 inhibitor R-(-)-rolipram. Herein we describe a small series of rolipram analogs that contain fluoro- or iodo-substituents that could be used as fluorine-18 PET or iodine-123 SPECT PDE4 radiotracers. This series was evaluated with an in vitro binding assay and a 4-(fluoromethyl) derivative of rolipram, MNI-617, was identified, with a five-fold increase in affinity for PDE4 (Kd =0.26nM) over R-(-)-rolipram (Kd =1.6nM). A deutero-analogue d2 -[(18) F]MNI-617 was radiolabeled and produced in 23% yield with high (>5Ci/mol) specific activity and evaluated in non-human primate, where it rapidly entered the brain, with SUVs between 4 and 5, and with a distribution pattern consistent with that of PDE4.

Imaging agents that target adenosine type2A (A2A ) receptors play an important role in evaluating new pharmaceuticals targeting these receptors, such as those currently being developed for the treatment of movement disorders like Parkinsons disease. They are also useful for monitoring progression and treatment efficacy by providing a noninvasive tool to map changes in A2A receptor density and function in neurodegenerative diseases. We previously described the successful evaluation of two A2A -specific radiotracers in both nonhuman primates and in subsequent human clinical trials: [(123) I]MNI-420 and [(18) F]MNI-444. Herein we describe the development of both of these radiotracers by selection from a series of A2A ligands, based on the pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine core of preladenant. Each of this series of 16 ligands was found to bind to recombinant human A2A receptor in the low nanomolar range, and of these 16, six were radiolabeled with either fluorine-18 or iodine-123 and evaluated in nonhuman primates. These initial invivo results resulted in the identification of 7-(2-(4-(4-(2-[(18) F]fluoroethoxy)phenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine ([(18) F]MNI-444) and 7-(2-(4-(2-fluoro-4-[(123) I]iodophenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-amine ([(123) I]MNI-420) as PET and SPECT radiopharmaceuticals for mapping A2A receptors in brain.

PubMed | Max Planck Institute for Human Cognitive and Brain Sciences, University of Leipzig, University Hospital Freiburg and Molecular Neuroimaging, Llc
Type: Clinical Trial, Phase II | Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine | Year: 2016

Neocortical atrophy reduces PET signal intensity, potentially affecting the diagnostic efficacy of -amyloid (A) brain PET imaging. This study investigated whether partial-volume effect correction (PVEC), adjusting for this atrophy bias, improves the accuracy of (18)F-florbetaben A PET.We analyzed (18)F-florbetaben PET and MRI data obtained from 3 cohorts. The first was 10 patients with probable Alzheimer disease (AD) and 10 age-matched healthy controls (HCs), the second was 31 subjects who underwent in vivo imaging and postmortem histopathology for A plaques, and the third was 5 subjects who underwent PET and MRI at baseline and 1 y later. The imaging data were coregistered and segmented. PVEC was performed using the voxel-based modified Mller-Grtner method (PVELab, SPM8). From the PET data, regional and composite SUV ratios (SUVRs) with and without PVEC were obtained. In the MRI data, mesial temporal lobe atrophy was determined by the Scheltens mesial temporal atrophy scale and gray matter volumes by voxel-based morphometry.In cohort 1, PVEC increased the effect on AD-versus-HC discrimination from a Cohen d value of 1.68 to 2.0 for composite SUVRs and from 0.04 to 1.04 for mesial temporal cortex SUVRs. The PVEC-related increase in mesial temporal cortex SUVR correlated with the Scheltens score (r = 0.84, P < 0.001), and that of composite SUVR correlated with the composite gray matter volume (r = -0.75, P < 0.001). In cohort 2, PVEC increased the correlation coefficient between mesial temporal cortex SUVR and histopathology score for A plaque load from 0.28 (P = 0.09) to 0.37 (P = 0.03). In cohort 3, PVEC did not affect the composite SUVR dynamics over time for the A-negative subject. This finding was in contrast to the 4 A-positive subjects, in 2 of whom PVEC changed the composite SUVR dynamics.The influence of PVEC on (18)F-florbetaben PET data is associated with the degree of brain atrophy. Thus, PVEC increases the ability of (18)F-florbetaben PET to discriminate between AD patients and HCs, to detect A plaques in the atrophic mesial temporal cortex, and potentially to evaluate changes in brain A load over time. As such, the use of PVEC should be considered for quantitative (18)F-florbetaben PET scans, especially in assessing patients with brain atrophy.

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