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2.
NPJ Parkinsons Dis ; 10(1): 42, 2024 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-38402233

RESUMO

Parkinson's disease (PD) is the fastest growing neurodegenerative disease, but at present there is no cure, nor any disease-modifying treatments. Synaptic biomarkers from in vivo imaging have shown promise in imaging loss of synapses in PD and other neurodegenerative disorders. Here, we provide new clinical insights from a cross-sectional, high-resolution positron emission tomography (PET) study of 30 PD individuals and 30 age- and sex-matched healthy controls (HC) with the radiotracer [11C]UCB-J, which binds to synaptic vesicle glycoprotein 2A (SV2A), and is therefore, a biomarker of synaptic density in the living brain. We also examined a measure of relative brain perfusion from the early part of the same PET scan. Our results provide evidence for synaptic density loss in the substantia nigra that had been previously reported, but also extend this to other early-Braak stage regions known to be affected in PD (brainstem, caudate, olfactory cortex). Importantly, we also found a direct association between synaptic density loss in the nigra and severity of symptoms in patients. A greater extent and wider distribution of synaptic density loss in PD patients with longer illness duration suggests that [11C]UCB-J PET can be used to measure synapse loss with disease progression. We also demonstrate lower brain perfusion in PD vs. HC groups, with a greater extent of abnormalities in those with longer duration of illness, suggesting that [11C]UCB-J PET can simultaneously provide information on changes in brain perfusion. These results implicate synaptic imaging as a useful PD biomarker for future disease-modifying interventions.

3.
Transl Oncol ; 37: 101767, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37657154

RESUMO

BACKGROUND: FDG PET/CT is a tool for assessing response to therapy in various cancers, and may provide an earlier biomarker of clinical response. We developed a novel semi-automated approach for analyzing FDG PET/CT images in patients with multiple myeloma (MM) to standardize FDG PET application. METHODS: Patients (n = 8) with relapsed/refractory MM from the Phase 2 study (NCT02899052) of venetoclax plus carfilzomib and dexamethasone underwent FDG PET/CT at baseline and up to two timepoints during treatment. Images were processed using an established automated segmentation algorithm, with the modification that a red marrow region in an unaffected lumbar vertebra was used to define background standardized uptake value normalized to lean body mass (SUL) threshold above which uptake was considered disease-specific uptake. This approach was compared to lesion segmentation, and to International Myeloma Working Group (IMWG) response criteria, including minimal residual disease (MRD). RESULTS: The two FDG PET analysis techniques agreed on evaluation of patient-level SULpeak for 67% of scans. In the metabolic response assessment per PET Response Criteria in Solid Tumors (PERCIST), the two techniques agreed in 75% of patients. Differences between techniques occurred in low-uptake lesions due to greater reader sensitivity to lesions with uptake marginally above background. PERCIST outcomes were generally in agreement with IMWC and MRD. CONCLUSIONS: This semi-automated analysis was in high agreement with standard approaches for detecting response to MM therapy. This proof-of-concept study suggests that larger studies should be conducted to confirm how FDG PET analysis may aid early response detection in MM.

4.
J Nucl Med ; 64(3): 444-451, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36175137

RESUMO

In vivo characterization of pathologic deposition of tau protein in the human brain by PET imaging is a promising tool in drug development trials of Alzheimer disease (AD). 6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine (18F-MK-6240) is a radiotracer with high selectivity and subnanomolar affinity for neurofibrillary tangles that shows favorable nonspecific brain penetration and excellent kinetic properties. The purpose of the present investigation was to develop a visual assessment method that provides both an overall assessment of brain tauopathy and regional characterization of abnormal tau deposition. Methods: 18F-MK-6240 scans from 102 participants (including cognitively normal volunteers and patients with AD or other neurodegenerative disorders) were reviewed by an expert nuclear medicine physician masked to each participant's diagnosis to identify common patterns of brain uptake. This initial visual read method was field-tested in a separate, nonoverlapping cohort of 102 participants, with 2 additional naïve readers trained on the method. Visual read outcomes were compared with semiquantitative assessments using volume-of-interest SUV ratio. Results: For the visual read, the readers assessed 8 gray-matter regions per hemisphere as negative (no abnormal uptake) or positive (1%-25% of the region involved, 25%-75% involvement, or >75% involvement) and then characterized the tau binding pattern as positive or negative for evidence of tau and, if positive, whether brain uptake was in an AD pattern. The readers demonstrated agreement 94% of the time for overall positivity or negativity. Concordance on the determination of regional binary outcomes (negative or positive) showed agreement of 74.3% and a Fleiss κ of 0.912. Using clinical diagnosis as the ground truth, the readers demonstrated a sensitivity of 73%-79% and specificity of 91%-93%, with a combined reader-concordance sensitivity of 80% and specificity of 93%. The average SUV ratio in cortical regions showed a robust correlation with visually derived ratings of regional involvement (r = 0.73, P < 0.0001). Conclusion: We developed a visual read algorithm for 18F-MK-6240 PET offering determination of both scan positivity and the regional degree of cortical involvement. These cross-sectional results show strong interreader concordance on both binary and regional assessments of tau deposition, as well as good sensitivity and excellent specificity supporting use as a tool for clinical trials.


Assuntos
Doença de Alzheimer , Encéfalo , Humanos , Estudos Transversais , Encéfalo/metabolismo , Doença de Alzheimer/metabolismo , Proteínas tau/metabolismo , Tomografia por Emissão de Pósitrons/métodos
5.
Sci Transl Med ; 14(658): eabk1051, 2022 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-35976998

RESUMO

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer's disease (AD). In this study, we quantified the in vivo expression of the endoplasmic reticulum stress marker, sigma 1 receptor (S1R), using [11C]SA4503 positron emission tomography (PET), the mitochondrial complex I (MC1) with [18F]BCPP-EF, and the presynaptic vesicular protein SV2A with [11C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and cerebral blood flow (CBF) measured with magnetic resonance imaging arterial spin labeling. Eight patients with AD were followed longitudinally to estimate the rate of change of the physiological and structural pathology markers with disease progression. The patients showed widespread increases in S1R (≤ 27%) and regional reduction in MC1 (≥ -28%) and SV2A (≥ -25%) radioligand binding, brain volume (≥ -23%), and CBF (≥ -26%). [18F]BCPP-EF PET MC1 binding (≥ -12%) and brain volumes (≥ -5%) showed progressive reductions over 12 to 18 months, suggesting that they both could be used as pharmacodynamic indicators in early-stage therapeutics trials. Associations of reduced MC1 and SV2A and increased S1R radioligand binding with reduced cognitive performance in AD, although exploratory, suggested a loss of metabolic functional reserve with disease. Our study thus provides in vivo evidence for widespread, clinically relevant cellular stress and bioenergetic abnormalities in early AD.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/patologia , Biomarcadores/metabolismo , Encéfalo/metabolismo , Circulação Cerebrovascular/fisiologia , Humanos , Imageamento por Ressonância Magnética , Mitocôndrias/metabolismo , Tomografia por Emissão de Pósitrons/métodos
6.
Mol Imaging Biol ; 24(5): 830-841, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35482146

RESUMO

PURPOSE: Bruton's tyrosine kinase (BTK) is a key component of B cell receptor (BCR) signaling, and as such a critical regulator of cell proliferation and survival. Aberrant BCR signaling is important in the pathogenesis of various B cell malignancies and autoimmune disorders. Here, we describe the development of a novel positron emission tomography (PET) tracer for imaging BTK expression and/or occupancy by small molecule therapeutics. METHODS: Radiochemistry was carried out by reacting the precursor with [18F]fluoride on a GE FX-FN TracerLab synthesis module to produce [18F]BTK-1 with a 6% decay-corrected radiochemical yield, 100 ± 6 GBq/µmol molar activity, and a radiochemical purity of 99%. Following intravenous administration of [18F]BTK-1 (3.63 ± 0.59 MBq, 0.084 ± 0.05 µg), 60-min dynamic images were acquired in two xenograft models: REC-1, an efficacious mantle cell lymphoma model, and U87MG, a non-efficacious glioblastoma model. Subsequent studies included vehicle, pretreatment (10 min prior to tracer injection), and displacement (30 min post-tracer injection) studies with different reversible BTK inhibitors to examine BTK binding. Human radiation dosimetry was estimated based on PET imaging in healthy rats. RESULTS: Uptake of [18F]BTK-1 was significantly higher in BTK expressing REC-1 tumors than non-BTK expressing U87MG tumors. Administration of BTK inhibitors prior to tracer administration blocked [18F]BTK-1 binding in the REC-1 tumor model consistent with [18F]BTK-1 binding to BTK. The predicted effective dose in humans was 0.0199 ± 0.0007 mSv/MBq. CONCLUSION: [18F]BTK-1 is a promising PET tracer for imaging of BTK, which could provide valuable information for patient selection, drug dose determination, and improving our understanding of BTK biology in humans.


Assuntos
Fluoretos , Inibidores de Proteínas Quinases , Humanos , Animais , Ratos , Adulto , Tirosina Quinase da Agamaglobulinemia/química , Tirosina Quinase da Agamaglobulinemia/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Antígenos de Linfócitos B , Tomografia por Emissão de Pósitrons
7.
Sci Rep ; 11(1): 7700, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33833333

RESUMO

GABAA-α5 subunit-containing receptors have been shown to play a key modulatory role in cognition and represent a promising drug target for cognitive dysfunction, as well as other disorders. Here we report on the preclinical and early clinical profile of a novel GABAA-α5 selective negative allosteric modulator (NAM), basmisanil, which progressed into Phase II trials for intellectual disability in Down syndrome and cognitive impairment associated with schizophrenia. Preclinical pharmacology studies showed that basmisanil is the most selective GABAA-α5 receptor NAM described so far. Basmisanil bound to recombinant human GABAA-α5 receptors with 5 nM affinity and more than 90-fold selectivity versus α1, α2, and α3 subunit-containing receptors. Moreover, basmisanil inhibited GABA-induced currents at GABAA-α5 yet had little or no effect at the other receptor subtypes. An in vivo occupancy study in rats showed dose-dependent target engagement and was utilized to establish the plasma exposure to receptor occupancy relationship. At estimated receptor occupancies between 30 and 65% basmisanil attenuated diazepam-induced spatial learning impairment in rats (Morris water maze), improved executive function in non-human primates (object retrieval), without showing anxiogenic or proconvulsant effects in rats. During the Phase I open-label studies, basmisanil showed good safety and tolerability in healthy volunteers at maximum GABAA-α5 receptor occupancy as confirmed by PET analysis with the tracer [11C]-Ro 15-4513. An exploratory EEG study provided evidence for functional activity of basmisanil in human brain. Therefore, these preclinical and early clinical studies show that basmisanil has an ideal profile to investigate potential clinical benefits of GABAA-α5 receptor negative modulation.


Assuntos
Agonistas de Receptores de GABA-A/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Regulação Alostérica , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Feminino , Células HEK293 , Voluntários Saudáveis , Humanos , Aprendizagem/efeitos dos fármacos , Macaca fascicularis , Tomografia por Emissão de Pósitrons , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Xenopus laevis
8.
J Cereb Blood Flow Metab ; 41(4): 771-779, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32501157

RESUMO

Mitochondrial complex I (MC-I) is an essential regulator of brain bioenergetics and can be quantified in the brain using PET radioligand 18F-BCPP-EF. Here we evaluate the test-retest reproducibility of 18F-BCPP-EF in humans, and assess the use of a non-invasive quantification method (standardised uptake value ratio - SUVR). Thirty healthy volunteers had a 90-min dynamic 18F-BCPP-EF scan with arterial blood sampling, five of which received a second scan to be included in the test-retest analysis. Time-activity curves (TAC) were analysed using multilinear analysis 1 (MA1) and the two-tissue compartment model (2TC) to estimate volumes of distribution (VT). Regional SUVR-1 values were calculated from the 70 to 90-min TAC data using the centrum semiovale as a pseudo reference region, and compared to kinetic analysis-derived outcome measures. The mean absolute test-retest variability of VT ranged from 12% to 18% across regions. Both DVR-1and SUVR-1 had improved test-retest variability in the range 2%-7%. SUVR-1 was highly correlated with DVR-1 (r2 = 0.97, n = 30). In conclusion, 18F-BCPP-EF has suitable test-retest reproducibility and can be used to quantify MC-I in clinical studies.


Assuntos
Encéfalo/diagnóstico por imagem , Complexo I de Transporte de Elétrons/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Piridazinas/química , Piridinas/química , Compostos Radiofarmacêuticos/química , Adulto , Idoso , Animais , Química Encefálica , Mapeamento Encefálico , Feminino , Voluntários Saudáveis , Humanos , Processamento de Imagem Assistida por Computador , Cinética , Macaca mulatta , Masculino , Pessoa de Meia-Idade , Piridazinas/síntese química , Piridinas/síntese química , Compostos Radiofarmacêuticos/síntese química , Reprodutibilidade dos Testes , Adulto Jovem
9.
Diagnostics (Basel) ; 12(1)2021 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-35054244

RESUMO

Magnetic resonance imaging (MRI) is a sensitive imaging modality for identifying inflammatory and/or demyelinating lesions, which is critical for a clinical diagnosis of MS and evaluating drug responses. There are many unique means of probing brain tissue status, including conventional T1 and T2 weighted imaging (T1WI, T2WI), T2 fluid attenuated inversion recovery (FLAIR), magnetization transfer, myelin water fraction, diffusion tensor imaging (DTI), phase-sensitive inversion recovery and susceptibility weighted imaging (SWI), but no study has combined all of these modalities into a single well-controlled investigation. The goals of this study were to: compare different MRI measures for lesion visualization and quantification; evaluate the repeatability of various imaging methods in healthy controls; compare quantitative susceptibility mapping (QSM) with myelin water fraction; measure short-term longitudinal changes in the white matter of MS patients and map out the tissue properties of the white matter hyperintensities using STAGE (strategically acquired gradient echo imaging). Additionally, the outcomes of this study were anticipated to aid in the choice of an efficient imaging protocol reducing redundancy of information and alleviating patient burden. Of all the sequences used, T2 FLAIR and T2WI showed the most lesions. To differentiate the putative demyelinating lesions from inflammatory lesions, the fusion of SWI and T2 FLAIR was used. Our study suggests that a practical and efficient imaging protocol combining T2 FLAIR, T1WI and STAGE (with SWI and QSM) can be used to rapidly image MS patients to both find lesions and study the demyelinating and inflammatory characteristics of the lesions.

10.
Ann Neurol ; 87(3): 329-338, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31953875

RESUMO

OBJECTIVE: Parkinson disease is characterized by motor and nonmotor symptoms, reduced striatal dopamine signaling, and loss of dopamine neurons in the substantia nigra. It is now known that the pathological process in Parkinson disease may begin decades before the clinical diagnosis and include a variety of neuronal alterations in addition to the dopamine system. METHODS: This study examined the density of all synapses with synaptic vesicle glycoprotein 2A (SV2A) in Parkinson disease subjects with mild bilateral disease (n = 12) and matched normal controls (n = 12) using in vivo high-resolution positron emission tomographic imaging as well as postmortem autoradiography in an independent sample with Parkinson disease (n = 15) and normal controls (n = 13) in the substantia nigra and putamen. RESULTS: A group-by-brain region interaction effect (F10, 22 = 3.52, p = 0.007) was observed in the primary brain areas with in vivo SV2A binding. Post hoc analyses revealed that the Parkinson disease group exhibited lower SV2A in the substantia nigra (-45%; p < 0.001), red nucleus (-31%; p = 0.03), and locus coeruleus (-17%; p = 0.03). Exploratory analyses also revealed lower SV2A binding in clinically relevant cortical areas. Using autoradiography, we confirmed lower SV2A in the substantia nigra (-17%; p < 0.005) and nonsignificant findings in the putamen (-4%; p = 0.06). INTERPRETATION: This work provides the first evidence of synaptic loss in brainstem nuclei involved in the pathogenesis of Parkinson disease in living patients. SV2A imaging holds promise for understanding synaptic changes central to the disease. Ann Neurol 2020;87:329-338.


Assuntos
Diagnóstico Precoce , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Putamen/patologia , Substância Negra/patologia , Sinapses/patologia , Autorradiografia , Estudos de Casos e Controles , Feminino , Neuroimagem Funcional , Humanos , Locus Cerúleo/patologia , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Tomografia por Emissão de Pósitrons , Putamen/metabolismo , Piridinas , Pirrolidinas , Núcleo Rubro/patologia , Substância Negra/metabolismo
11.
J Nucl Med ; 61(1): 96-103, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31324712

RESUMO

Mitochondrial complex 1 is involved in maintaining brain bioenergetics; σ-1 receptor responds to neuronal stress; and synaptic vesicle protein 2A reflects synaptic integrity. Expression of each of these proteins is altered in neurodegenerative diseases. Here, we characterize the kinetic behavior of 3 PET radioligands-18F-BCPP-EF, 11C-SA-4503, and 11C-UCB-J-for the measurement of mitochondrial complex 1, σ-1 receptor, and synaptic vesicle protein 2A, respectively, and determine appropriate analysis workflows for their application in future studies of the in vivo molecular pathology of these diseases. Methods: Twelve human subjects underwent dynamic PET scans with each radioligand, including associated arterial blood sampling. A range of kinetic models was investigated to identify an optimal kinetic analysis method for each radioligand and a suitable acquisition duration. Results: All 3 radioligands readily entered the brain and yielded heterogeneous uptake consistent with the known distribution of the targets. The optimal models determined for the regional estimates of volume of distribution were multilinear analysis 1 (MA1) and the 2-tissue-compartment model for 18F-BCPP-EF, MA1 for 11C-SA-4503, and both MA1 and the 1-tissue-compartment model for 11C-UCB-J. Acquisition times of 70, 80, and 60 min for 18F-BCPP-EF, 11C-SA-4503, 11C-UCB-J, respectively, provided good estimates of regional volume of distribution values. An effect of age was observed on 18F-BCPP-EF and 11C-UCB-J signal in the caudate. Conclusion: These ligands can be assessed for their potential to stratify patients or monitor the progression of molecular neuropathology in neurodegenerative diseases.


Assuntos
Encéfalo/diagnóstico por imagem , Piperazinas/química , Tomografia por Emissão de Pósitrons , Piridazinas/química , Piridinas/química , Pirrolidinonas/química , Compostos Radiofarmacêuticos/química , Adulto , Fatores Etários , Idoso , Envelhecimento , Retículo Endoplasmático/metabolismo , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Cinética , Ligantes , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/diagnóstico por imagem , Fatores de Tempo
12.
Brain Imaging Behav ; 13(2): 354-365, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30259405

RESUMO

As drug discovery and development in Neuroscience push beyond symptom management to disease modification, neuroimaging becomes a key area of translational research that enables measurements of the presence of drugs and downstream physiological consequences of drug action within the living brain. As such, neuroimaging can be used to help optimize decision-making processes throughout the various phases of drug development. Positron Emission Tomography (PET) is a functional imaging technique that allows the quantification and visualization of biochemical processes, by monitoring the time dependent distribution of molecules labelled with short-lived positron-emitting isotopes. This review focuses on the application of PET to support CNS drug development, particularly in the early clinical phases, by allowing us to measure tissue exposure, target engagement, and pharmacological activity. We will also discuss the application of PET imaging as tools to image the pathological hallmarks of disease and evaluate the potential disease-modifying effect of candidate drugs in slowing disease progression.


Assuntos
Encéfalo/efeitos dos fármacos , Desenvolvimento de Medicamentos/métodos , Tomografia por Emissão de Pósitrons/métodos , Biomarcadores , Humanos , Doenças Neurodegenerativas/diagnóstico por imagem
13.
J Nucl Med ; 59(12): 1877-1884, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30097505

RESUMO

The availability of tau PET radioligands enables quantitative assessment of tau density and distribution in the human brain. We evaluated the kinetics of a novel radioligand, 18F-RO-948 (previously referred to as 18F-RO6958948), and its ability to identify tau positivity in individual patients with mild Alzheimer disease (AD). Methods: Eleven subjects with amyloid-positive mild AD, 5 amyloid-negative older control subjects (OC), and 5 younger control subjects (YC) completed 1 or 2 (4 AD and 5 OC) PET scans with 18F-RO-948 for 90, 120, or 200 min. The kinetics of the radioligand was evaluated with standard compartmental and noncompartmental models (with plasma data in 70% of cases), tissue-reference methods, and SUV ratio. These approaches were applied to assess the ability of 18F-RO-948 to discriminate AD subjects from OC subjects. Results: The plasma reference graphical analysis appeared to be the optimal method of quantification for 18F-RO-948, yielding strictly time-consistent values of distribution volume and distribution volume ratio at 90 min against the analyses at 120 and 200 min. The reference tissue graphical analysis and SUV ratio were cross-validated against plasma reference graphical analysis. Test-retest evaluation showed excellent reproducibility. A proposed novel index of tau load, the regional tau-positive fraction, showed high values in the medial and lateral temporal and parietal regions in AD and successfully separated AD subjects from OC and YC subjects with a significant margin. Conclusion:18F-RO-948 appears to be a promising radioligand for quantitative imaging of tau in the brain of AD patients.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Neuroimagem Funcional/métodos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Proteínas tau/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Radioisótopos de Flúor , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Ensaio Radioligante , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Adulto Jovem
14.
J Nucl Med ; 59(12): 1869-1876, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29728519

RESUMO

11C-RO-963, 11C-RO-643, and 18F-RO-948 (previously referred to as 11C-RO6924963, 11C-RO6931643, and 18F-RO6958948, respectively) have been reported as promising PET tracers for tau imaging based on in vitro and preclinical PET data. Here we describe the first, to our knowledge, human evaluation of these novel radiotracers. Methods: Amyloid PET-positive Alzheimer disease (AD) subjects and younger controls each received 2 different tau tracers. Dynamic 90-min scans were obtained after bolus injection of 11C-RO-963, 11C-RO-643, or 18F-RO-948. Arterial blood sampling was performed on 11 healthy controls and 11 AD subjects. Regions were defined on MR images, and PET data were quantified by plasma reference graphical analysis (for total distribution volume) and target cerebellum ratio (SUV ratios of 60- to 90-min frames). SUV ratio images were also analyzed voxelwise. Five older controls each underwent 2 scans with 18F-RO-948 for evaluation of test-retest variability. Four AD subjects underwent a repeated 18F-RO-948 scan 6-22 mo after the first scan. Six additional healthy controls (3 men and 3 women; age range, 41-67 y) each underwent 1 whole-body dosimetry scan with 18F-RO-948. Results: In younger controls, SUVpeak was observed in the temporal lobe with values of approximately 3.0 for 11C-RO-963, 1.5 for 11C-RO-643, and 3.5 for 18F-RO-948. Over all brain regions and subjects, the trend was for 18F-RO-948 to have the highest SUVpeak, followed by 11C-RO-963 and then 11C-RO-643. Regional analysis of SUV ratio and total distribution volume for 11C-RO-643 and 18F-RO-948 clearly discriminated the AD group from the healthy control groups. Compartmental modeling confirmed that 11C-RO-643 had lower brain entry than either 11C-RO-963 or 18F-RO-948 and that 18F-RO-948 showed better contrast between (predicted) areas of high versus low tau accumulation. Thus, our subsequent analysis focused on 18F-RO-948. Both voxelwise and region-based analysis of 18F-RO-948 binding in healthy controls versus AD subjects revealed multiple areas where AD subjects significantly differed from healthy controls. Of 22 high-binding regions, 13 showed a significant group difference (after ANOVA, F(1,21) = 45, P < 10-5). Voxelwise analysis also revealed a set of symmetric clusters where AD subjects had higher binding than healthy controls (threshold of P < 0.001, cluster size > 50). Conclusion:18F-RO-948 demonstrates characteristics superior to 11C-RO-643 and 11C-RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties of 18F-RO-948 compare favorably with other existing tau PET tracers.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Proteínas tau/metabolismo , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Mapeamento Encefálico , Radioisótopos de Carbono , Estudos de Casos e Controles , Feminino , Radioisótopos de Flúor , Humanos , Masculino , Pessoa de Meia-Idade , Doses de Radiação , Ensaio Radioligante , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual
15.
Alzheimers Res Ther ; 9(1): 25, 2017 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-28359327

RESUMO

BACKGROUND: 18F-THK5351 is a quinoline-derived tau imaging agent with high affinity to paired helical filaments (PHF). However, high levels of 18F-THK5351 retention in brain regions thought to contain negligible concentrations of PHF raise questions about the interpretation of the positron emission tomography (PET) signals, particularly given previously described interactions between quinolone derivatives and monoamine oxidase B (MAO-B). Here, we tested the effects of MAO-B inhibition on 18F-THK5351 brain uptake using PET and autoradiography. METHODS: Eight participants (five mild cognitive impairment, two Alzheimer's disease, and one progressive supranuclear palsy) had baseline 18F-AZD4694 and 18F-THK5351 scans in order to quantify brain amyloid and PHF load, respectively. A second 18F-THK5351 scan was conducted 1 week later, 1 h after a 10-mg oral dose of selegiline. Three out of eight patients also had a third 18F-THK5351 scan 9-28 days after the selegiline administration. The primary outcome measure was standardized uptake value (SUV), calculated using tissue radioactivity concentration from 50 to 70 min after 18F-THK5351 injection, normalizing for body weight and injected radioactivity. The SUV ratio (SUVR) was determined using the cerebellar cortex as the reference region. 18F-THK5351 competition autoradiography studies in postmortem tissue were conducted using 150 and 500 nM selegiline. RESULTS: At baseline, 18F-THK5351 SUVs were highest in the basal ganglia (0.64 ± 0.11) and thalamus (0.62 ± 0.14). In the post-selegiline scans, the regional SUVs were reduced on average by 36.7% to 51.8%, with the greatest reduction noted in the thalamus (51.8%) and basal ganglia (51.4%). MAO-B inhibition also reduced 18F-THK5351 SUVs in the cerebellar cortex (41.6%). The SUVs remained reduced in the three patients imaged at 9-28 days. Tissue autoradiography confirmed the effects of MAO-B inhibition on 18F-THK5351 uptake. CONCLUSIONS: These results indicate that the interpretation of 18F-THK5351 PET images, with respect to tau, is confounded by the high MAO-B availability across the entire brain. In addition, the heterogeneous MAO-B availability across the cortex may limit the interpretation of 18F-THK5351 scans using reference region methods.


Assuntos
Aminopiridinas/farmacocinética , Encéfalo/diagnóstico por imagem , Radioisótopos de Flúor/farmacocinética , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Quinolinas/farmacocinética , Selegilina/farmacologia , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Autorradiografia , Ligação Competitiva , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Interações Medicamentosas , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/metabolismo , Proteínas tau/metabolismo
16.
J Nucl Med ; 58(7): 1124-1131, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27908967

RESUMO

18F-AV-1451 is currently the most widely used of several experimental tau PET tracers. The objective of this study was to evaluate 18F-AV-1451 binding with full kinetic analysis using a metabolite-corrected arterial input function and to compare parameters derived from kinetic analysis with SUV ratio (SUVR) calculated over different imaging time intervals. Methods:18F-AV-1451 PET brain imaging was completed in 16 subjects: 4 young healthy volunteers (YHV), 4 aged healthy volunteers (AHV), and 8 Alzheimer disease (AD) subjects. Subjects were imaged for 3.5 h, with arterial blood samples obtained throughout. PET data were analyzed using plasma and reference tissue-based methods to estimate the distribution volume, binding potential (BPND), and SUVR. BPND and SUVR were calculated using the cerebellar cortex as a reference region and were compared across the different methods and across the 3 groups (YHV, AHV, and AD). Results: AD demonstrated increased 18F-AV-1451 retention compared with YHV and AHV based on both invasive and noninvasive analyses in cortical regions in which paired helical filament tau accumulation is expected in AD. A correlation of R2 > 0.93 was found between BPND (130 min) and SUVR-1 at all time intervals. Cortical SUVR curves reached a relative plateau around 1.0-1.2 for YHV and AHV by approximately 50 min, but increased in AD by up to approximately 20% at 110-130 min and approximately 30% at 160-180 min relative to 80-100 min. Distribution volume (130 min) was lower by 30%-35% in the YHV than AHV. Conclusion: Our data suggest that although 18F-AV-1451 SUVR curves do not reach a plateau and are still increasing in AD, an SUVR calculated over an imaging window of 80-100 min (as currently used in clinical studies) provides estimates of paired helical filament tau burden in good correlation with BPND, whereas SUVR sensitivity to regional cerebral blood changes needs further investigation.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Carbolinas/farmacocinética , Modelos Biológicos , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo , Idoso , Doença de Alzheimer/diagnóstico por imagem , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Simulação por Computador , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Cinética , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/farmacocinética , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição Tecidual
17.
Drug Discov Today ; 22(1): 140-147, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27693713

RESUMO

Tremendous breakthroughs are being made in cancer drug discovery and development. However, such breakthroughs come at a high financial cost. At a time when there is increasing pressure on drug pricing, in part because of increased life expectancy, it is more important than ever to drive new therapeutics towards patients as efficiently as possible. In this review we discuss the applications of molecular imaging in oncology drug development, with a focus on its ability to enable better early decision making, to increase efficiency and thereby to lower costs.


Assuntos
Antineoplásicos , Descoberta de Drogas/métodos , Imagem Molecular/métodos , Antineoplásicos/economia , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Análise Custo-Benefício , Custos de Medicamentos , Descoberta de Drogas/economia , Humanos , Imagem Molecular/economia , Distribuição Tecidual
18.
Eur J Nucl Med Mol Imaging ; 44(3): 382-391, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27633250

RESUMO

PURPOSE: In Alzheimer's disease (AD), increased metabolism of monoamines by monoamine oxidase type B (MAO-B) leads to the production of toxic reactive oxygen species (ROS), which are thought to contribute to disease pathogenesis. Inhibition of the MAO-B enzyme may restore brain levels of monoaminergic neurotransmitters, reduce the formation of toxic ROS and reduce neuroinflammation (reactive astrocytosis), potentially leading to neuroprotection. Sembragiline (also referred as RO4602522, RG1577 and EVT 302 in previous communications) is a potent, selective and reversible inhibitor of MAO-B developed as a potential treatment for AD. METHODS: This study assessed the relationship between plasma concentration of sembragiline and brain MAO-B inhibition in patients with AD and in healthy elderly control (EC) subjects. Positron emission tomography (PET) scans using [11C]-L-deprenyl-D2 radiotracer were performed in ten patients with AD and six EC subjects, who received sembragiline each day for 6-15 days. RESULTS: At steady state, the relationship between sembragiline plasma concentration and MAO-B inhibition resulted in an Emax of ∼80-90 % across brain regions of interest and in an EC50 of 1-2 ng/mL. Data in patients with AD and EC subjects showed that near-maximal inhibition of brain MAO-B was achieved with 1 mg sembragiline daily, regardless of the population, whereas lower doses resulted in lower and variable brain MAO-B inhibition. CONCLUSIONS: This PET study confirmed that daily treatment of at least 1 mg sembragiline resulted in near-maximal inhibition of brain MAO-B enzyme in patients with AD.


Assuntos
Acetamidas/uso terapêutico , Doença de Alzheimer/diagnóstico por imagem , Inibidores da Monoaminoxidase/farmacocinética , Tomografia por Emissão de Pósitrons , Pirrolidinonas/uso terapêutico , Acetamidas/sangue , Acetamidas/farmacocinética , Administração Oral , Idoso , Doença de Alzheimer/tratamento farmacológico , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/administração & dosagem , Inibidores da Monoaminoxidase/uso terapêutico , Ligação Proteica , Pirrolidinonas/sangue , Pirrolidinonas/farmacocinética
19.
J Cereb Blood Flow Metab ; 37(6): 2137-2148, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27466376

RESUMO

[11C]Ro15-4513 has been introduced as a positron emission tomography radioligand to image the GABAAα5 receptor subtype thought to be important in learning, memory and addiction. However, the in vivo selectivity of the ligand remains unknown and a full assessment of different analysis approaches has yet to be performed. Using human heterologous competition data, with [11C]Ro15-4513 and the highly selective GABAAα5 selective negative allosteric modulator Basmisanil (RG1662), we quantify the GABAAα5 selectivity of [11C]Ro15-4513, assess the validity of reference tissues and evaluate the performance of four different kinetic analysis methods. The results show that [11C]Ro15-4513 has high but not complete selectivity for GABAAα5, with α5 representing around 60-70% of the specific binding in α5 rich regions. Competition data indicate that the cerebellum and pons are essentially devoid of α5 signal and might be used as reference regions under certain conditions. Off-target non-selective binding to other GABAA subtypes means that the choice of analysis method and the interpretation of outcome measures must be considered carefully. We discuss the merits of two tissue compartmental model analyses to derive both VT and VS, band-pass spectral analysis for estimation of [Formula: see text] and the simplified reference tissue model for estimation of [Formula: see text].


Assuntos
Azidas/química , Benzodiazepinas/química , Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Receptores de GABA-A/metabolismo , Ligação Competitiva , Encéfalo/diagnóstico por imagem , Voluntários Saudáveis , Humanos , Masculino , Ligação Proteica , Ensaio Radioligante , Sensibilidade e Especificidade
20.
Brain ; 139(Pt 4): 1252-64, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26984188

RESUMO

While emerging evidence suggests that neuroinflammation plays a crucial role in Alzheimer's disease, the impact of the microglia response in Alzheimer's disease remains a matter of debate. We aimed to study microglial activation in early Alzheimer's disease and its impact on clinical progression using a second-generation 18-kDa translocator protein positron emission tomography radiotracer together with amyloid imaging using Pittsburgh compound B positron emission tomography. We enrolled 96 subjects, 64 patients with Alzheimer's disease and 32 controls, from the IMABio3 study, who had both (11)C-Pittsburgh compound B and (18)F-DPA-714 positron emission tomography imaging. Patients with Alzheimer's disease were classified as prodromal Alzheimer's disease (n = 38) and Alzheimer's disease dementia (n = 26). Translocator protein-binding was measured using a simple ratio method with cerebellar grey matter as reference tissue, taking into account regional atrophy. Images were analysed at the regional (volume of interest) and at the voxel level. Translocator protein genotyping allowed the classification of all subjects in high, mixed and low affinity binders. Thirty high+mixed affinity binders patients with Alzheimer's disease were dichotomized into slow decliners (n = 10) or fast decliners (n = 20) after 2 years of follow-up. All patients with Alzheimer's disease had an amyloid positive Pittsburgh compound B positron emission tomography. Among controls, eight had positive amyloid scans (n = 6 high+mixed affinity binders), defined as amyloidosis controls, and were analysed separately. By both volumes of interest and voxel-wise comparison, 18-kDa translocator protein-binding was higher in high affinity binders, mixed affinity binders and high+mixed affinity binders Alzheimer's disease groups compared to controls, especially at the prodromal stage, involving the temporo-parietal cortex. Translocator protein-binding was positively correlated with Mini-Mental State Examination scores and grey matter volume, as well as with Pittsburgh compound B binding. Amyloidosis controls displayed higher translocator protein-binding than controls, especially in the frontal cortex. We found higher translocator protein-binding in slow decliners than fast decliners, with no difference in Pittsburgh compound B binding. Microglial activation appears at the prodromal and possibly at the preclinical stage of Alzheimer's disease, and seems to play a protective role in the clinical progression of the disease at these early stages. The extent of microglial activation appears to differ between patients, and could explain the overlap in translocator protein binding values between patients with Alzheimer's disease and amyloidosis controls.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Radioisótopos de Flúor , Microglia/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Pirazóis , Pirimidinas , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Encéfalo/patologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
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