Andrew Stephens

Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer's disease: Phase 3 study

Evaluation of brain β‐amyloid by positron emission tomography (PET) imaging can assist in the diagnosis of Alzheimer disease (AD) and other dementias.

High-affinity RNA ligands to human α-thrombin

Systematic Evolution of Ligands by EXponential enrichment (SELEX) was used to isolate from a population of 10(13) RNA molecules two classes of high affinity RNAs that bind specifically to human alpha-thrombin. Class I RNAs are represented by a 24-nucleotide RNA (RNA 16.24), and class II RNAs are represented by a 33-nucleotide RNA (RNA 27.33). RNA 16.24 inhibits thrombin-catalyzed fibrin clot formation in vitro. Secondary structures are proposed for these RNAs, revealing a novel stem-loop structure for RNA 16.24, comprised of an unusually large 16-nucleotide loop. Mutants of RNA 16.24 were generated to investigate structural features critical to high-affinity binding. Phosphate modification with ethylnitrosourea identified regions of the RNAs necessary for electrostatic interactions. Competition with heparin suggests that these RNAs bind the electropositive heparin-binding site of thrombin. These ligands represent a novel class of thrombin inhibitors that may be suitable for therapeutic or diagnostic applications.

Nucleic acid ligands of tissue target

This invention discloses high-affinity oligonucleotide ligands to complex tissue targets, specifically nucleic acid ligands having the ability to bind to complex tissue targets, and the methods for obtaining such ligands. Tissue targets comprise cells, subcellular components, aggregates or cells, collections of cells, and higher ordered structures. Specifically, nucleic acid ligands to blood vessels are described.

Specific PET Imaging of xC− Transporter Activity Using a 18F-Labeled Glutamate Derivative Reveals a Dominant Pathway in Tumor Metabolism

Purpose:18F-labeled small molecules targeting adaptations of tumor metabolism possess the potential for early tumor detection with high sensitivity and specificity by positron emission tomography (PET) imaging. Compounds tracing deranged pathways other than glycolysis may have advantages in situations where 2-[18F]fluoro-2-deoxy-d-glucose (FDG) has limitations. The aim of this study was the generation of a metabolically stable 18F-labeled glutamate analogue for PET imaging of tumors. Experimental Design: Derivatives of l-glutamate were investigated in cell competition assays to characterize the responsible transporter. An automated radiosynthesis was established for the most promising candidate. The resulting 18F-labeled PET tracer was characterized in a panel of in vitro and in vivo tumor models. Tumor specificity was investigated in the turpentine oil-induced inflammation model in rats. Results: A fluoropropyl substituted glutamate derivative showed strong inhibition in cell uptake assays. The radiosynthesis was established for (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (BAY 94-9392). Tracer uptake studies and analysis of knockdown cells showed specific transport of BAY 94-9392 via the cystine/glutamate exchanger designated as system xC−. No metabolites were observed in mouse blood and tumor cells. PET imaging with excellent tumor visualization and high tumor to background ratios was achieved in preclinical tumor models. In addition, BAY 94-9392 did not accumulate in inflammatory lesions in contrast to FDG. Conclusions: BAY 94-9392 is a new tumor-specific PET tracer which could be useful to examine system xC− activity in vivo as a possible hallmark of tumor oxidative stress. Both preclinical and clinical studies are in progress for further characterization. Clin Cancer Res; 17(18); 6000–11. ©2011 AACR.

Aβ imaging with 18F-florbetaben in prodromal Alzheimer's disease: a prospective outcome study

Background We assessed the clinical utility of β-amyloid (Aβ) imaging with 18F-florbetaben (FBB) in mild cognitive impairment (MCI) by evaluating its prognostic accuracy for progression to Alzheimers disease (AD), comparing semiquantitative with visual scan assessment, and exploring the relationships among Aβ, hippocampal volume (HV) and memory over time. Methods 45 MCI underwent FBB positron emission tomography, MRI and neuropsychological assessment at baseline and 2 years and clinical follow-up at 4 years. Positive FBB (FBB+), defined by a cortical to cerebellar cortex standardised uptake value ratio (SUVR) ≥1.45, was compared with visual assessment by five readers. Amnestic MCI (aMCI) was defined by a composite episodic memory (EM) Z-score of <−1.5. Results At baseline, 24 (53%) MCI were FBB+. Majority reads agreed with SUVR classification (κ 0.96). In 2 years, 18 (75%) FBB+ progressed to AD compared with 2 (9.5%) FBB−, yielding a predictive accuracy of 83% (95% CI 61% to 94%). Four FBB− developed non-AD dementia. Predictive accuracies of HV (58% (95% CI 42% to 73%)) and aMCI status (73% (95% CI 58% to 81%)) were lower. Combinations did not improve accuracy. By 4 years, 21 (87.5%) FBB+ had AD whereas 5 (24%) FBB− had non-AD dementia yielding a predictive accuracy of 94% (95% CI 74% to 99%). While the strong baseline association between FBB SUVR and EM declined over 2 years, the association between EM and HV became stronger. FBB SUVR increased 2.2%/year in FBB+ with no change in FBB−. Conclusions 18F-florbetaben Aβ imaging facilitates accurate detection of prodromal AD. As neurodegeneration progresses, and in contrast with the early stages of the disease, hippocampal atrophy and not Aβ, seems to drive memory decline. Trial registration number NCT01138111.

Age dependence of brain β-amyloid deposition in Down syndrome: An [18F]florbetaben PET study

Objective:To investigate brain &bgr;-amyloid binding in subjects with Down syndrome (DS) using [18F]florbetaben PET imaging. Methods:Thirty-nine subjects with DS (46.3 ± 4.7 years) were assessed with [18F]florbetaben PET imaging. Three blinded independent readers assessed the scans to provide a visual analysis. The primary quantitative imaging outcome was a standardized uptake value ratio (SUVR) obtained for 6 brain regions. Cognitive status was evaluated using the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID). Results:[18F]Florbetaben uptake was correlated with age (p < 0.0001, R2 = 0.39); 90% of scans in subjects with DS aged 50 years or older (SUVR = 1.62 ± 0.26), 53% in those aged 45 to 49 years (SUVR = 1.43 ± 0.16), and 7% in those aged 40 to 45 years (SUVR = 1.27 ± 0.11) were visually assessed as positive. Visual and quantitative assessments were highly related (&khgr;2 = 11.3823, p = 0.0007; Cohen &kgr; = 0.58). Only 2 of 34 participants were considered to have dementia by the DSQIID. Conclusions:Brain &bgr;-amyloid binding, as measured by [18F]florbetaben, increases with age in DS. Subjects with DS who have no evidence of dementia demonstrate brain &bgr;-amyloid binding in vivo, suggesting that [18F]florbetaben PET imaging may detect &bgr;-amyloid in this at-risk population.

Impact of Training Method on the Robustness of the Visual Assessment of 18F-Florbetaben PET Scans: Results from a Phase-3 Study.

Training for accurate image interpretation is essential for the clinical use of β-amyloid PET imaging, but the role of interpreter training and the accuracy of the algorithm for routine visual assessment of florbetaben PET scans are unclear. The aim of this study was to test the robustness of the visual assessment method for florbetaben scans, comparing efficacy readouts across different interpreters and training methods and against a histopathology standard of truth (SoT). Methods: Analysis was based on data from an international open-label, nonrandomized, multicenter phase-3 study in patients with or without dementia (ClinicalTrials.gov: NCT01020838). Florbetaben scans were assessed visually and quantitatively, and results were compared with amyloid plaque scores. For visual assessment, either in-person training (n = 3 expert interpreters) or an electronic training method (n = 5 naïve interpreters) was used. Brain samples from participants who died during the study were used to determine the histopathologic SoT using Bielschowsky silver staining (BSS) and immunohistochemistry for β-amyloid plaques. Results: Data were available from 82 patients who died and underwent postmortem histopathology. When visual assessment results were compared with BSS + immunohistochemistry as SoT, median sensitivity was 98.2% for the in-person–trained interpreters and 96.4% for the e-trained interpreters, and median specificity was 92.3% and 88.5%, respectively. Median accuracy was 95.1% and 91.5%, respectively. On the basis of BSS only as the SoT, median sensitivity was 98.1% and 96.2%, respectively; median specificity was 80.0% and 76.7%, respectively; and median accuracy was 91.5% and 86.6%, respectively. Interinterpreter agreement (Fleiss κ) was excellent (0.89) for in-person–trained interpreters and very good (0.71) for e-trained interpreters. Median intrainterpreter agreement was 0.9 for both in-person–trained and e-trained interpreters. Visual and quantitative assessments were concordant in 88.9% of scans for in-person–trained interpreters and in 87.7% of scans for e-trained interpreters. Conclusion: Visual assessment of florbetaben images was robust in challenging scans from elderly end-of-life individuals. Sensitivity, specificity, and interinterpreter agreement were high, independent of expertise and training method. Visual assessment was accurate and reliable for detection of plaques using BSS and immunohistochemistry and well correlated with quantitative assessments.

First Clinical Results of (d)-18F-Fluoromethyltyrosine (BAY 86-9596) PET/CT in Patients with Non–Small Cell Lung Cancer and Head and Neck Squamous Cell Carcinoma

(d)-18F-fluoromethyltyrosine (d-18F-FMT), or BAY 86-9596, is a novel 18F-labeled tyrosine derivative rapidly transported by the l-amino acid transporter (LAT-1), with a faster blood pool clearance than the corresponding l-isomer. The aim of this study was to demonstrate the feasibility of tumor detection in patients with non–small cell lung cancer (NSCLC) or head and neck squamous cell cancer (HNSCC) compared with inflammatory and physiologic tissues in direct comparison to 18F-FDG. Methods: 18 patients with biopsy-proven NSCLC (n = 10) or HNSCC (n = 8) were included in this Institutional Review Board–approved, prospective multicenter study. All patients underwent 18F-FDG PET/CT scans within 21 d before d-18F-FMT PET/CT. For all patients, safety and outcome data were assessed. Results: No adverse reactions were observed related to d-18F-FMT. Fifty-two lesions were 18F-FDG–positive, and 42 of those were malignant (34 histologically proven and 8 with clinical reference). Thirty-two of the 42 malignant lesions were also d-18F-FMT–positive, and 10 lesions had no tracer uptake above the level of the blood pool. Overall there were 34 true-positive, 8 true-negative, 10 false-negative, and only 2 false-positive lesions for d-18F-FMT, whereas 18F-FDG was true-positive in 42 lesions, with 10 false-positive and only 2 false-negative, resulting in a lesion-based detection rate for d-18F-FMT and 18F-FDG of 77% and 95%, respectively, with an accuracy of 78% for both tracers. A high d-18F-FMT tumor–to–blood pool ratio had a negative correlation with overall survival (P = 0.050), whereas the 18F-FDG tumor–to–blood pool ratio did not correlate with overall survival. Conclusion: d-18F-FMT imaging in patients with NSCLC and HNSCC is safe and feasible. The presented preliminary results suggest a lower sensitivity but higher specificity for d-18F-FMT over 18F-FDG, since there is no d-18F-FMT uptake in inflammation. This increased specificity may be particularly beneficial in areas with endemic granulomatous disease and may improve clinical management. Further clinical investigations are needed to determine its clinical value and relevance for the prediction of survival prognosis.

Alzheimer's biomarkers in daily practice (ABIDE) project: Rationale and design

The Alzheimers biomarkers in daily practice (ABIDE) project is designed to translate knowledge on diagnostic tests (magnetic resonance imaging [MRI], cerebrospinal fluid [CSF], and amyloid positron emission tomography [PET]) to daily clinical practice with a focus on mild cognitive impairment (MCI)

New protein deposition tracers in the pipeline

Traditional nuclear medicine ligands were designed to target cellular receptors or transporters with a binding pocket and a defined structure–activity relationship. More recently, tracers have been developed to target pathological protein aggregations, which have less well-defined structure–activity relationships. Aggregations of proteins such as tau, α-synuclein, and β-amyloid (Aβ) have been identified in neurodegenerative diseases, including Alzheimer’s disease (AD) and other dementias, and Parkinson’s disease (PD). Indeed, Aβ deposition is a hallmark of AD, and detection methods have evolved from coloured dyes to modern 18F-labelled positron emission tomography (PET) tracers. Such tracers are becoming increasingly established in routine clinical practice for evaluation of Aβ neuritic plaque density in the brains of adults who are being evaluated for AD and other causes of cognitive impairment. While similar in structure, there are key differences between the available compounds in terms of dosing/dosimetry, pharmacokinetics, and interpretation of visual reads. In the future, quantification of Aβ-PET may further improve its utility. Tracers are now being developed for evaluation of tau protein, which is associated with decreased cognitive function and neurodegenerative changes in AD, and is implicated in the pathogenesis of other neurodegenerative diseases. While no compound has yet been approved for tau imaging in clinical use, it is a very active area of research. Development of tau tracers comprises in-depth characterisation of existing radiotracers, clinical validation, a better understanding of uptake patterns, test-retest/dosimetry data, and neuropathological correlations with PET. Tau imaging may allow early, more accurate diagnosis, and monitoring of disease progression, in a range of conditions. Another marker for which imaging modalities are needed is α-synuclein, which has potential for conditions including PD and dementia with Lewy bodies. Efforts to develop a suitable tracer are ongoing, but are still in their infancy. In conclusion, several PET tracers for detection of pathological protein depositions are now available for clinical use, particularly PET tracers that bind to Aβ plaques. Tau-PET tracers are currently in clinical development, and α-synuclein protein deposition tracers are at early stage of research. These tracers will continue to change our understanding of complex disease processes.