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NEW HAVEN, CT, United States

Barthel H.,University of Leipzig | Gertz H.-J.,University of Leipzig | Dresel S.,Helios Hospital Berlin Buch | Peters O.,Charite - 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 ClinicalTrials.gov, 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. Source


Grant
Agency: Department of Energy | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 100.00K | Year: 2007

This project will develop a fast, automated, and accurate software processing package that will objectively yield striatal quantitative uptake values for evaluating Parkinson's disease (PD) diagnosis and progression. This fully automated, Objective Striatal Analysis (OSA) package will evaluate subjects referred for SPECT neuroreceptor imaging studies, with a sensitivity and specificity higher than currently possible by visual inspection or manual image processing methods. By employing OSA, it will be possible to analyze archival scans, which otherwise would require months of manual labor. Without any user interaction, OSA will: (1) reorient the reconstructed brain volume along the cantho-meatal line; (2) identify axial slices with striatal activity; (3) place templates on the left and right caudate, the putamen, and the occipital background regions, following set rules for movement of regions; and (4) extract count density data for the determination of regional striatal. The required algorithms will be coded into a software package, and the results will be applied to groups of patients and healthy volunteers. The results will be compared to results obtained by manually analyzing the same subject groups. Commercial Applications and other Benefits as described by the awardee: The OSA for Parkinson¿s Disease should lead to more accurate and efficient clinical studies requiring fewer subjects. It would then be possible to evaluate new radiopharmaceutical and therapy agents without obfuscating the results by improper or insufficiently-tested image processing methods. In addition, the technology should serve as a model for the development of similar objective algorithms to fully assess radiopharmaceuticals in other disorders, such as Alzheimer¿s disease.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 258.42K | Year: 2007

DESCRIPTION (provided by applicant): The goal of this research project is to define the structure and radioactive label for ligands that will per-mit quantitative measurement of amyloid sites in living brain by external imaging with positron (PET) or single photon (SPECT) emission tomography. A radiotracer that bound specifically to amyloid would be of great utility in diagnosis, monitoring treatment, and research of such Alzheimer's disease and related gerontological disorders. Based on preliminary in vitro binding results using a classical structure-activity relationship approach, we found that certain benzoxazole derivatives showed affinity to amyloid protein in the nanomolar range. In this application we propose to test the following hypotheses: 1) Novel Indole and benzimidazole derivatives with appropriately functionalized aromatic substituents will favor binding to amyloid Ab(1-40) protein; and 2) radio-labeling with PET or SPECT radionuclides will provide a molecular probe that can image amyloid protein in vivo. Specifically, this project poses the following specific aims AIM #1. Measure binding to amyloid protein of a group of benzothiazole derivatives already synthesized to expand the structure-activity relationship in this class of compounds. Nine candidates will be tested by in vitro homogenate displacement binding against radiolabeled ligand for amyloid protein. AIM #2. Synthesize a defined library of halogenated heterocyclic analogs and screen for binding to amyloid protein. The working hypothesis is that the successful structure will incorporate the elements of an electron-donating group on an aromatic ring (A) attached to an aromatic heterocyclic 5/6 ring system (B/C). Eleven candidates will be synthesized and tested by in vitro homogenate displacement binding against radiolabeled ligand for amyloid protein. AIM #3. Radiolabel the best candidates with radioactive I-123 or F-18 and determine their in vivo uptake properties in nonhuman primates. The candidates with binding affinities better than 10 nM will be radiolabeled and their lipophilicity will be measured as the octanol-buffer partition coefficient (log D). Compounds with log D less than 3.5 will be studied by dynamic regional brain imaging in nonhuman primates by with SPECT or PET. We estimate that four compounds per year will be imaged. The causes of Alzheimer's disease (AD) are still unclear, but postmortem examination of patient's brains reveal abundant senile plaques composed of amyloid-beta (Aa) peptides and neurofibrillary tangles formed by filaments of highly phosphorylated tau protein. Thus, a radiotracer that bound specifically to Aa protein would provide an in vivo measure of this process and would find application in the study, diagnosis, and treatment of psychiatric disorders. In this application we proposed to develop a selective compound to quantify these plaques in human.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 500.00K | Year: 2008

DESCRIPTION (provided by applicant): The goal of this research project is to validate in humans a new ligand with picomolar affinity for the serotonin transporter. It will permit quantitative measurement of serotonin transporter (5- HTT) sites in living br ain by imaging with single photon emission tomography (SPECT). The serotonin transporter is known to play a critical role in several physiological and pathophysiological processes, including depression, anxiety, seasonal affective disorder, bulimia, and ps ychosis, as demonstrated by post-mortem data, clinical efficacy of therapies affecting this target site, and imaging studies. A radiotracer that binds specifically to 5-HTT is of great utility in diagnosis, monitoring treatment, and research of these disor ders. There is a need for better tracers that allow quantitation in areas of the brain with low 5-HTT densities such as the cortex.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 500.00K | Year: 2006

The goal of this research project is to define the structure and radioactive label for ligands that will permit quantitative measurement of the peripheral benzodiazepine receptor (PBR ) in living brain by external imaging with positron (PET) or single photon (SPECT) emission tomography. A radio-tracer binding specifically to PBR would be of great utility in diagnosis, monitoring treatment, and etiological research of neuropsychiatric disorders such as brain damage, neurodegenerative diseases, anxiety and stress disorders. The PBR is thought to be associated with many biological functions, including the regulation of cellular proliferation, immunomodulation, porphyrin transport, heme biosynthesis, anion transport, regulation of steroidogenesis, and apoptosis. For example, increases in PBR have been observed in brain tissue from patients with HIV/AIDS, Alzheimer's disease, Huntington's disease, multiple sclerosis, and gliosis. A PET study in patients with AIDS showed increased cortical and subcortical PBR receptor binding, supporting the role of glial cell activation in HIV patients with dementia. This study highlights the limitations of current radioligands used and points out the need to further optimize quantitation of PBR. We found that certain indole glyoxylamide derivatives showed nanomolar affinity to PBR. However, brain uptake of two of them labeled with 123I was low in nonhuman primate. Key questions posed by these results are: a) Can PBR affinity and selectivity be increased while reducing lipophilicity with different heterocyclic substituents? And b) are the homogenate binding results applicable to in vivo uptake and distribution? In this application we propose to test the following hypotheses: 1) N,N-dialkyl indolylglyoxylamides with appropriately functionalized heterocyclic substituents on the 2-position of indole will favor binding to PBR relative to CBR; and 2) introduction of these heteroaromatic rings will alter the lipophilicity of our compounds so as to have lower nonspecific binding and higher brain uptake. We will synthesize a series of N,N-dialkyl-2-heterocyclic substituted indolylglyoxylamides. The candidates with binding affinities below 10 nM for PBR and selectivity vis-a-vis CBR above 100 will be radiolabeled with F-18 or I-123 and their lipophilicity (log D) will be measured. In vivo binding will be measured in nonhuman primates by imaging regional brain distribution of the radio-tracer under control conditions and with specific pharmacological challenges. Correlation of log D, in vitro affinity, and in vivo selectivity will be evaluated. At the conclusion of this project period, we expect to have identified a radioligand suitable for imaging the PBR in NeuroAIDS, dementia and other diseases.

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