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1.
J Nucl Med ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712323

RESUMO

18F-PI-2620 is a positron emission tomography (PET) tracer with high binding affinity for aggregated tau, a key pathologic feature of Alzheimer's disease (AD) and other neurodegenerative disorders. Preclinically, 18F-PI-2620 binds to both, 3R and 4R tau isoforms. The purpose of this first-in-human study was to evaluate the ability of 18F-PI-2620 to detect tau pathology in AD patients using PET imaging, as well as to assess its safety and tolerability of this new tau PET tracer. Methods: Participants with clinical diagnosis of probable AD and healthy controls (HC) underwent dynamic 18F-PI-2620 PET imaging for 180 min. 18F-PI-2620 binding was assessed visually and quantitatively using Distribution Volume Ratios (DVR) estimated from non-invasive tracer kinetics and standardized uptake value ratios (SUVR) measured at different time points post-injection (p.i.) with the cerebellar cortex as the reference region. Time-activity curves and SUVR were assessed in AD and HC, as well as DVR and SUVR correlations and effect size (Cohen's d) over time. Results: 18F-PI-2620 showed peak brain uptake around 5 min p.i. and fast wash-out in non-target regions. In AD subjects, focal asymmetric uptake was evident in temporal and parietal lobes, precuneus, and posterior cingulate cortex. DVR and SUVR in these regions were significantly higher in AD compared to HC. Very low background signal was observed in HC. 18F-PI-2620 administration was safe and well tolerated. SUVR time activity curves in most regions and subjects achieved a secular equilibrium after 40 min p.i.. A strong correlation (R 2 > 0.93) was found between non-invasive DVR and SUVR for all imaging windows starting >30 min p.i.. Similar effect sizes between AD and HC groups were obtained across the different imaging windows. 18F-PI-2620 uptake in neocortical regions was significantly correlated with the degree of cognitive impairment. Conclusion: Initial clinical data obtained in AD and HC demonstrate the high image quality with excellent signal-to-noise of 18F-PI-2620 PET for imaging tau deposition in AD subjects. Non-invasive quantification using DVR and SUVR for 30 min imaging windows between 30-90 min p.i., e.g. 45-75 min, provides robust and significant discrimination between AD and HC subjects. 18F-PI-2620 uptake in expected regions is highly correlated to neurocognitive performance.

2.
J Nucl Med ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712324

RESUMO

18F-PI-2620 is a next generation tau positron emission tomography (PET)-tracer that has demonstrated ability to image the spatial distribution of suspected tau pathology. The objective of this study was to assess the tracer biodistribution, dosimetry and quantitative methods of 18F-PI-2620 in the human brain. Full kinetic modelling approaches to quantify tau load were investigated. Non-invasive kinetic modeling approaches and semi-quantitative methods were evaluated against the full tracer kinetics. Finally, the reproducibility of PET measurements from test and retest scans was assessed. Methods: Three healthy controls (HC) and 4 Alzheimer disease (AD) subjects underwent two dynamic PET scans including arterial sampling. Distribution volume ratio (DVR) was estimated using full tracer kinetics (2 Tissue Compartment (2TC) models, Logan Graphical Analysis (LGA)) and non-invasive kinetic models (Non-Invasive Logan Graphical Analysis (NI-LGA) and the multilinear reference tissue model (MRTM2)). Standardized uptake value ratio (SUVR) was determined at different imaging windows after injection. Correlation between DVR and SUVR, effect size (Cohen's d) and test-retest variability (TRV) were evaluated. Additionally, 6 HC subjects received one tracer administration and underwent whole-body PET for dosimetry calculation. Organ doses and the whole-body effective dose were calculated using OLINDA 2.0. Results: Strong correlation was found across different kinetic models (R2 >0.97) and between DVR(2TC) and SUVRs between 30 to 90 min with R2>0.95. Secular equilibrium was reached around 40 min post injection (p.i.) in most regions and subjects. The TRV and effect size for the SUVR across different regions was similar at 30-60 min (TRV=3.8%, d=3.80), 45-75 min (TRV=4.3%, d=3.77) and 60-90 min (TRV=4.9%, d=3.73) and increased at later time points. Elimination was via the hepatobiliary and urinary system. The whole-body effective dose was determined to be 33.3±2.1 µSv/MBq for an adult female and 33.1±1.4 µSv/MBq for an adult male with a 1.5 hour urinary bladder voiding interval. Conclusion: 18F-PI-2620 exhibits fast kinetics, suitable dosimetry and low TRV. DVR measured using the 2TC model with arterial sampling correlated strongly with DVR measured by NI-LGA, MRTM2 and SUVR. SUVR can be used for 18F-PI-2620 PET quantification of tau deposits avoiding arterial blood sampling. Static 18F-PI-2620 PET scans between 45-75min p.i. provide excellent quantification accuracy, large effect size and low TRV.

3.
Nucl Med Biol ; 72-73: 45-48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31330411

RESUMO

PURPOSE: 4-(3S)-3-[5-(2-[18F]-fluoroethoxy)pyridin-3-yl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]-piperidin-3-yl}carbonyl)amino]propanoic acid ([18F]GP1) is a radiotracer developed for targeted imaging of activated platelet glycoprotein IIb/IIIa receptors with positron emission tomography/computed tomography (PET/CT) in acute thromboembolism. We evaluated here radiation dosimetry of [18F]GP1 in humans. PROCEDURES: We studied 30 subjects (10 with deep vein thrombosis, 10 with pulmonary embolism, and 10 with arterial thromboembolism) who had signs or symptoms of acute thromboembolism, and were confirmed to have thromboembolic foci by imaging studies. Dynamic whole-body PET/CT images were acquired for up to 140 min after injection of 250 MBq of [18F]GP1. Radiation absorbed dose and effective dose were calculated using the OLINDA/EXM software. RESULTS: [18F]GP1 PET images showed high initial uptake of the tracer in the heart, spleen, kidney, and liver. [18F]GP1 activity was cleared by hepatobiliary and urinary excretion. The organ receiving the highest radiation absorbed dose (mGy/MBq) was the urinary bladder (0.0884 ±â€¯0.0458), followed by upper large intestine (0.0498 ±â€¯0.0189), small intestine (0.0454 ±â€¯0.0166), and kidneys (0.0350 ±â€¯0.0231). The effective dose (mSv/MBq) was 0.0212 ±â€¯0.0027 (ICRP 103). ED was not significantly different between the three disease groups (p = 0.94). A 45-minute voiding reduced the urinary bladder wall radiation dose to 0.0495 ±â€¯0.0140 mGy/MBq, and effective dose (ICRP 103) to 0.0186 ±â€¯0.0030. CONCLUSIONS: [18F]GP1 has favorable radiation dosimetry profile for clinical PET/CT imaging. The ED is comparable to commonly used 18F PET tracers.

4.
J Nucl Med ; 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171595

RESUMO

Purpose: The aim of this study was development of an improved positron emission tomography (PET) radiotracer for measuring xC- activity with increased tumor uptake and reduced uptake in inflammatory cells compared to (S)-4-(3-18F-Fluoropropyl)-L-glutamic acid (18F-FSPG). Experimental design: A racemic glutamate derivative, 18F-hGTS13 was evaluated in cell culture and animal tumor models. 18F-hGTS13 was separated into C5-epimers and the corresponding 18F-hGTS13-isomer1 and 18F-hGTS13-isomer2 evaluated in H460 tumor bearing rats. Preliminary studies investigate the cellular uptake of 18F-hGTS13-isomer2 in multiple immune cell populations and states. Results: 18F-hGTS13 demonstrated excellent H460 tumor visualization with high tumor-to-background ratios, confirmed by ex vivo biodistribution studies. Tumor associated radioactivity of 18F-hGTS13 (7.5±0.9%ID/g, n = 3) was significantly higher than with 18F-FSPG (4.6±0.7%ID/g, n = 3, P = 0.01). 18F-hGTS13-isomer2 exhibited excellent H460 tumor visualization (6.3±1.1%ID/g, n-3), and significantly reduced uptake in multiple immune cell populations relative to 18F-FSPG. 18F-hGTS13-isomer2 exhibited increased liver uptake relative to 18F-FSPG (4.6±0.8%ID/g vs. 0.7±0.01%ID/g) limiting its application in hepatocellular carcinoma. Conclusion: 18F-hGTS13-isomer2 is a new PET radiotracer for molecular imaging of xC- activity which may provide information regarding tumor oxidation states. 18F-hGTS13-isomer2 has potential for clinical translation for imaging cancers of the thorax due to the low background signal in healthy tissue.

5.
Clin Cancer Res ; 25(8): 2471-2482, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30651275

RESUMO

PURPOSE: Drug resistance is a major obstacle for the effective treatment of patients with high-grade serous ovarian cancer (HGSOC). Currently, there is no satisfactory way to identify patients with HGSOC that are refractive to the standard of care. Here, we propose the system xc - radiotracer (4S)-4-(3-[18F]fluoropropyl)-l-glutamate ([18F]FSPG) as a non-invasive method to measure upregulated antioxidant pathways present in drug-resistant HGSOC. EXPERIMENTAL DESIGN: Using matched chemotherapy sensitive and resistant ovarian cancer cell lines, we assessed their antioxidant capacity and its relation to [18F]FSPG uptake, both in cells and in animal models of human ovarian cancer. We identified the mechanisms driving differential [18F]FSPG cell accumulation and evaluated [18F]FSPG tumor uptake as predictive marker of treatment response in drug-resistant tumors. RESULTS: High intracellular glutathione (GSH) and low reactive oxygen species corresponded to decreased [18F]FSPG cell accumulation in drug-resistant versus drug-sensitive cells. Decreased [18F]FSPG uptake in drug-resistant cells was a consequence of changes in intracellular cystine, a key precursor in GSH biosynthesis. In vivo, [18F]FSPG uptake was decreased nearly 80% in chemotherapy-resistant A2780 tumors compared with parental drug-sensitive tumors, with nonresponding tumors displaying high levels of oxidized-to-reduced GSH. Treatment of drug-resistant A2780 tumors with doxorubicin resulted in no detectable change in tumor volume, GSH, or [18F]FSPG uptake. CONCLUSIONS: This study demonstrates the ability of [18F]FSPG to detect upregulated antioxidant pathways present in drug-resistant cancer. [18F]FSPG may therefore enable the identification of patients with HGSOC that are refractory to standard of care, allowing the transferal of drug-resistant patients to alternative therapies, thereby improving outcomes in this disease.

6.
Cancer Res ; 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30401715

RESUMO

The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no non-invasive tools exist to measure this system in patients. The cystine/glutamate antiporter system xc- maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here we show that tumor cell retention of a system xc--specific positron emission tomography radiotracer, (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [18F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U-13C6, U-15N2]cystine isotopic tracing. In vivo, treatment with the chemotherapeutic doxorubicin decreased [18F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [18F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment.

7.
J Nucl Med ; 2018 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-29959214

RESUMO

18F-GP1 is a derivative of elarofiban with a high affinity to activated platelet glycoprotein IIb/IIIa (GPIIb/IIIa) and favorable in vivo characteristics for thrombus imaging in preclinical models. We aimed to explore the detection rate of thromboembolic foci with 18F-GP1 positron emission tomography/computed tomography (PET/CT) in patients with acute venous thromboembolism (VTE), and to evaluate the safety, biodistribution, pharmacokinetics, and metabolism of 18F-GP1. Methods: We studied patients who had signs or symptoms of acute deep vein thrombosis (DVT) of the leg or acute pulmonary embolism (PE) within 14 days prior to 18F-GP1 PET/CT, and had thromboembolic foci confirmed by conventional imaging (n = 10 for DVT and n = 10 for PE). Dynamic whole-body PET/CT images were acquired for up to 140 minutes after injection of 250 MBq of 18F-GP1. Results:18F-GP1 PET/CT was well tolerated without any drug-related adverse events, and showed high initial uptake in spleen, kidney, and blood pool, followed by rapid clearance. The overall image quality was excellent and allowed interpretation in all patients. 18F-GP1 PET/CT identified thromboembolic foci in all 20 patients with either DVT or PE. Vessel-level analysis revealed that 18F-GP1 PET/CT detected 89% (68/76) of vessels with DVT, and 60% (146/245) for PE. Importantly, 18F-GP1 PET/CT showed increased uptake in 32 vessels that were not detected by conventional imaging, of which 25 were located in distal veins of the lower extremity in 12 patients. A positive correlation was found between 18F-GP1 uptake and P-selectin-positive circulating platelets (r = 0.656, P = 0.002). Conclusion:18F-GP1 is a promising PET tracer for imaging acute VTE in patients. 18F-GP1 PET/CT may identify thrombi in distal veins of the leg, where conventional imaging has limitations.

8.
Mol Imaging ; 17: 1536012117749052, 2018 Jan-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29350098

RESUMO

Thrombus formation can lead to heart attacks, stroke and pulmonary embolism, which are major causes of mortality. Current standard diagnostic imaging methods detect anatomic abnormalities such as vascular flow impairment but have limitations. By using a targeted molecular imaging approach critical components of a pathology can be selectively visualized and exploited for an improved diagnosis and patient management. The GPIIb/IIIa receptor is abundantly and specifically exposed on activated platelets and is the key receptor in thrombus formation. This commentary describes the current status of GPIIb/IIIa-based PET imaging approaches with a focus on the recently published preclinical data of the small-molecule PET tracer 18F-GP1. Areas of future research and potential clinical applications are discussed that may lead to an improved detection of critical thromboembolic events and an optimization of available antithrombotic therapies by tracking activated platelets.


Assuntos
Plaquetas , Trombose , Humanos , Imagem Molecular , Complexo Glicoproteico GPIIb-IIIa de Plaquetas , Tomografia por Emissão de Pósitrons
9.
J Nucl Med ; 59(7): 1104-1110, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29175981

RESUMO

Accurate amyloid PET quantification is necessary for monitoring amyloid-ß accumulation and response to therapy. Currently, most of the studies are analyzed using the static SUV ratio (SUVR) approach because of its simplicity. However, this approach may be influenced by changes in cerebral blood flow (CBF) or radiotracer clearance. Full tracer kinetic models require arterial blood sampling and dynamic image acquisition. The objectives of this work were, first, to validate a noninvasive kinetic modeling approach for 18F-florbetaben PET using an acquisition protocol with the best compromise between quantification accuracy and simplicity and, second, to assess the impact of CBF changes and radiotracer clearance on SUVRs and noninvasive kinetic modeling data in 18F-florbetaben PET. Methods: Using data from 20 subjects (10 patients with probable Alzheimer dementia and 10 healthy volunteers), the nondisplaceable binding potential (BPND) obtained from the full kinetic analysis was compared with the SUVR and with noninvasive tracer kinetic methods (simplified reference tissue model and multilinear reference tissue model 2). Various approaches using shortened or interrupted acquisitions were compared with the results of the full acquisition (0-140 min). Simulations were performed to assess the effect of CBF and radiotracer clearance changes on SUVRs and noninvasive kinetic modeling outputs. Results: An acquisition protocol using time windows of 0-30 and 120-140 min with appropriate interpolation of the missing time points provided the best compromise between patient comfort and quantification accuracy. Excellent agreement was found between BPND obtained using the full protocol and BPND obtained using the dual-window protocol (for multilinear reference tissue model 2, BPND [dual-window] = 0.01 + 1.00·BPND [full], R2 = 0.97; for simplified reference tissue model, BPND [dual-window] = 0.05 + 0.92·BPND [full], R2 = 0.93). Simulations showed a limited impact of CBF and radiotracer clearance changes on multilinear reference tissue model parameters and SUVR. Conclusion: This study demonstrated accurate noninvasive kinetic modeling of 18F-florbetaben PET data using a dual-window acquisition, thus providing a good compromise between quantification accuracy, scan duration, and patient burden. The influence of CBF and radiotracer clearance changes on amyloid-ß load estimates was small. For most clinical research applications, the SUVR approach is appropriate. However, for longitudinal studies in which maximum quantification accuracy is desired, this noninvasive dual-window acquisition with kinetic analysis is recommended.

10.
Neuroimage Clin ; 15: 325-332, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28560157

RESUMO

INTRODUCTION: Standardized uptake value ratios (SUVRs) calculated from cerebral cortical areas can be used to categorize 18F-Florbetaben (FBB) PET scans by applying appropriate cutoffs. The objective of this work was first to generate FBB SUVR cutoffs using visual assessment (VA) as standard of truth (SoT) for a number of reference regions (RR) (cerebellar gray matter (GCER), whole cerebellum (WCER), pons (PONS), and subcortical white matter (SWM)). Secondly, to validate the FBB PET scan categorization performed by SUVR cutoffs against the categorization made by post-mortem histopathological confirmation of the Aß presence. Finally, to evaluate the added value of SUVR cutoff categorization to VA. METHODS: SUVR cutoffs were generated for each RR using FBB scans from 143 subjects who were visually assessed by 3 readers. SUVR cutoffs were validated in 78 end-of life subjects using VA from 8 independent blinded readers (3 expert readers and 5 non-expert readers) and histopathological confirmation of the presence of neuritic beta-amyloid plaques as SoT. Finally, the number of correctly or incorrectly classified scans according to pathology results using VA and SUVR cutoffs was compared. RESULTS: Composite SUVR cutoffs generated were 1.43 (GCER), 0.96 (WCER), 0.78 (PONS) and 0.71 (SWM). Accuracy values were high and consistent across RR (range 83-94% for histopathology, and 85-94% for VA). SUVR cutoff performed similarly as VA but did not improve VA classification of FBB scans read either by expert readers or the majority read but provided higher accuracy than some non-expert readers. CONCLUSION: The accurate scan classification obtained in this study supports the use of VA as SoT to generate site-specific SUVR cutoffs. For an elderly end of life population, VA and SUVR cutoff categorization perform similarly in classifying FBB scans as Aß-positive or Aß-negative. These results emphasize the additional contribution that SUVR cutoff classification may have compared with VA performed by non-expert readers.


Assuntos
Compostos de Anilina , Encéfalo/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Tomografia por Emissão de Pósitrons/métodos , Estilbenos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Classificação , Estudos de Coortes , Feminino , Humanos , Masculino , Doente Terminal
11.
ACS Med Chem Lett ; 8(3): 304-309, 2017 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-28337321

RESUMO

The neuropeptide Y (NPY) Y1 receptor (Y1R) selective radioligand (R)-Nα-(2,2-diphenylacetyl)-Nω-[4-(2-[18F]fluoropropanoylamino)butyl]aminocarbonyl-N-(4-hydroxybenzyl)argininamide ([18F]23), derived from the high-affinity Y1R antagonist BIBP3226, was developed for imaging studies of Y1R-positive tumors. Starting from the argininamide core bearing amine-functionalized spacer moieties, a series of fluoropropanoylated and fluorobenzoylated derivatives was synthesized and studied for Y1R affinity. The fluoropropanoylated derivative 23 displayed high affinity (Ki = 1.3 nM) and selectivity toward Y1R. Radiosynthesis was accomplished via 18F-fluoropropanoylation, yielding [18F]23 with excellent stability in mice; however, the biodistribution study revealed pronounced hepatobiliary clearance with high accumulation in the gall bladder (>100 %ID/g). Despite the unfavorable biodistribution, [18F]23 was successfully used for imaging of Y1R positive MCF-7 tumors in nude mice. Therefore, we suggest [18F]23 as a lead for the design of PET ligands with optimized physicochemical properties resulting in more favorable biodistribution and higher Y1R-dependent enrichment in mammary carcinoma.

12.
J Nucl Med ; 58(7): 1094-1099, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28302764

RESUMO

Thromboembolic diseases such as myocardial infarction, stroke, transient ischemic attacks, and pulmonary embolism are major causes of morbidity and mortality worldwide. Glycoprotein IIb/IIIa (GPIIb/IIIa) is the key receptor involved in platelet aggregation and is a validated target for therapeutic approaches and diagnostic imaging. The aim of this study was to develop and characterize a specific small-molecule tracer for PET imaging that binds with high affinity to GPIIb/IIIa receptors and has suitable pharmacokinetic properties to overcome limitations of previous approaches. Methods: Binding of 18F-GP1 to GPIIb/IIIa receptors was investigated in competition binding assays and autoradiography using a fresh cardiac thrombus from an explanted human heart. The clot-to-blood ratio for 18F-GP1 was investigated by an in vitro blood flow model. Biodistribution and thrombus detection was investigated in cynomolgus monkeys after insertion of a roughened catheter into either the vena cava or the aorta. Results:18F-GP1 is an 18F-labeled small molecule for PET imaging of thrombi. The half maximal inhibitory concentration of 18F-GP1 to GPIIb/IIIa was 20 nM. 18F-GP1 bound to thrombi with a mean clot-to-blood ratio of 95. Binding was specific and can be displaced by excess nonradioactive derivative. Binding was not affected by anticoagulants such as aspirin or heparin. 18F-GP1 showed rapid blood clearance and a low background after intravenous injection in cynomolgus monkeys. Small arterial, venous thrombi, thrombotic depositions on damaged endothelial surface, and small cerebral emboli were detected in vivo by PET imaging. Conclusions:18F-GP1 binds specifically with high affinity to the GPIIb/IIIa receptor involved in platelet aggregation. Because of its favorable preclinical characteristics, 18F-GP1 is currently being investigated in a human clinical study.


Assuntos
Glutamina/análogos & derivados , Lauratos/farmacocinética , Imagem Molecular/métodos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Trombose/diagnóstico por imagem , Trombose/metabolismo , Animais , Feminino , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacocinética , Glutamina/farmacocinética , Humanos , Marcação por Isótopo/métodos , Macaca fascicularis , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
13.
J Nucl Med ; 58(8): 1300-1306, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28183994

RESUMO

Accurate measurement of changes in amyloid-ß (Aß) deposition over time is important in longitudinal studies, particularly in anti-Aß therapeutic trials. To achieve this, the optimal reference region (RR) must be selected to reduce variance of Aß PET measurements, allowing early detection of treatment efficacy. The aim of this study was to determine the RR that allows earlier detection of subtle Aß changes using 18F-florbetaben PET. Methods: Forty-five patients with mild cognitive impairment (mean age ± SD, 72.69 ± 6.54 y; 29 men/16 women) who underwent up to 3 18F-florbetaben scans were included. Baseline scans were visually classified as high (Aß+) or low (Aß-) amyloid. Six cortical regions were quantified using a standardized region-of-interest atlas applied to the spatially normalized gray matter image obtained from segmentation of the baseline T1-weighted volumetric MRI. Four RRs (cerebellar gray matter [CGM], whole cerebellum [WCER], pons, and subcortical white matter [SWM]) were studied. The SUV ratio (SUVR) for each RR was calculated by dividing cortex activity by RR activity, with a composite SUVR averaged over 6 cortical regions. SUVR increase from baseline to 1 and 2 y, and percentage Aß deposition per year, were assessed across Aß+ and Aß- groups. Results: SUVs for any RR were not significantly different over time. Percentage Aß accumulation per year derived from composite SUVR was 0.10 ± 1.72 (Aß-) and 1.36 ± 1.98 (Aß+) (P = 0.02) for CGM and 0.13 ± 1.47 and 1.32 ± 1.75 (P = 0.01), respectively, for WCER. Compared with baseline, the composite SUVR increase in Aß+ scans was significantly larger than in Aß- scans at 1 y (P = 0.04 [CGM]; P = 0.03 [WCER]) and 2 y (P = 0.02 [CGM]; P = 0.01 [WCER]) using these 2 RRs. Significant SUVR changes using the pons as the RR were detected only at 2 y (P = 0.46 [1 y], P = 0.001 [2 y]). SUVR using the SWM as the RR showed no significant differences at either follow-up (P = 0.39 [1 y], P = 0.09 [2 y]). Conclusion: RR selection influences reliable early measurement of Aß changes over time. Compared with SWM and pons, which do not fulfil the RR requirements and have limited sensitivity to detect Aß changes, cerebellar RRs are recommended for 18F-florbetaben PET because they allow earlier detection of Aß accumulation.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina , Tomografia por Emissão de Pósitrons/normas , Estilbenos , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Compostos de Anilina/metabolismo , Transporte Biológico , Feminino , Humanos , Estudos Longitudinais , Masculino , Padrões de Referência , Estilbenos/metabolismo
14.
Psychiatry Res Neuroimaging ; 265: 98-101, 2017 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-28024844

RESUMO

Today, the use of biomarkers such as amyloid-specific positron emission tomography (PET) tracers and information derived from cerebrospinal fluid (CSF) can support the diagnosis of Alzheimer's disease (AD) as an indicator for the presence of amyloid pathology. We here show that the PET signal of the 18F-labelled tracer florbetaben (NeuraCeq™), that binds to amyloid-beta plaques, inversely correlates with CSF levels of Aß42, another biomarker for AD. Results from the two biomarkers were concordant in 35 out of 38 subjects. In 7 AD subjects (20%) at least one biomarker was inconsistent with the clinical diagnosis. This confirms known limitations of the clinical AD diagnosis and highlights the potential of biomarker-assisted diagnosis to improve accuracy.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Compostos de Anilina , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons/métodos , Estilbenos , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
15.
EJNMMI Radiopharm Chem ; 1(1): 11, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29564387

RESUMO

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 ß-amyloid (Aß) have been identified in neurodegenerative diseases, including Alzheimer's disease (AD) and other dementias, and Parkinson's disease (PD). Indeed, Aß 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 Aß 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 Aß-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 Aß 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.

16.
Mol Imaging Biol ; 18(6): 924-934, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27677886

RESUMO

PURPOSE: Non-invasive imaging is central to hepatocellular carcinoma (HCC) diagnosis; however, conventional modalities are limited by smaller tumors and other chronic diseases that are often present in patients with HCC, such as cirrhosis. This pilot study evaluated the feasibility of (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) positron emission tomography (PET)/X-ray computed tomography (CT) to image HCC. [18F]FSPG PET/CT was compared to standard-of-care (SOC) magnetic resonance imaging (MRI) and CT, and [11C]acetate PET/CT, commonly used in this setting. We report the largest cohort of HCC patients imaged to date with [18F]FSPG PET/CT and present the first comparison to [11C]acetate PET/CT and SOC imaging. This study represents the first in a US HCC population, which is distinguished by different underlying comorbidities than non-US populations. PROCEDURES: xC- transporter RNA and protein levels were evaluated in HCC and matched liver samples from The Cancer Genome Atlas (n = 16) and a tissue microarray (n = 83). Eleven HCC patients who underwent prior MRI or CT scans were imaged by [18F]FSPG PET/CT, with seven patients also imaged with [11C]acetate PET/CT. RESULTS: xC- transporter RNA and protein levels were elevated in HCC samples compared to background liver. Over 50 % of low-grade HCCs and ~70 % of high-grade tumors exceeded background liver protein expression. [18F]FSPG PET/CT demonstrated a detection rate of 75 %. [18F]FSPG PET/CT also identified an HCC devoid of typical MRI enhancement pattern. Patients scanned with [18F]FSPG and [11C]acetate PET/CT exhibited a 90 and 70 % detection rate, respectively. In dually positive tumors, [18F]FSPG accumulation consistently resulted in significantly greater tumor-to-liver background ratios compared with [11C]acetate PET/CT. CONCLUSIONS: [18F]FSPG PET/CT is a promising modality for HCC imaging, and larger studies are warranted to examine [18F]FSPG PET/CT impact on diagnosis and management of HCC. [18F]FSPG PET/CT may also be useful for phenotyping HCC tumor metabolism as part of precision cancer medicine.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Glutamatos/química , Ácido Glutâmico/química , Neoplasias Hepáticas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Acetatos/química , Adulto , Idoso , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Radioisótopos de Carbono , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/química , Análise de Sequência de RNA , Análise Serial de Tecidos
17.
PLoS One ; 11(2): e0148628, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26890637

RESUMO

PURPOSE: (S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid (18F-FSPG) is a novel radiopharmaceutical for Positron Emission Tomography (PET) imaging. It is a glutamate analogue that can be used to measure xC- transporter activity. This study was performed to assess the feasibility of 18F-FSPG for imaging orthotopic brain tumors in small animals and the translation of this approach in human subjects with intracranial malignancies. EXPERIMENTAL DESIGN: For the small animal study, GS9L glioblastoma cells were implanted into brains of Fischer rats and studied with 18F-FSPG, the 18F-labeled glucose derivative 18F-FDG and with the 18F-labeled amino acid derivative 18F-FET. For the human study, five subjects with either primary or metastatic brain cancer were recruited (mean age 50.4 years). After injection of 300 MBq of 18F-FSPG, 3 whole-body PET/Computed Tomography (CT) scans were obtained and safety parameters were measured. The three subjects with brain metastases also had an 18F-FDG PET/CT scan. Quantitative and qualitative comparison of the scans was performed to assess kinetics, biodistribution, and relative efficacy of the tracers. RESULTS: In the small animals, the orthotopic brain tumors were visualized well with 18F-FSPG. The high tumor uptake of 18F-FSPG in the GS9L model and the absence of background signal led to good tumor visualization with high contrast (tumor/brain ratio: 32.7). 18F-FDG and 18F-FET showed T/B ratios of 1.7 and 2.8, respectively. In the human pilot study, 18F-FSPG was well tolerated and there was similar distribution in all patients. All malignant lesions were positive with 18F-FSPG except for one low-grade primary brain tumor. In the 18F-FSPG-PET-positive tumors a similar T/B ratio was observed as in the animal model. CONCLUSIONS: 18F-FSPG is a novel PET radiopharmaceutical that demonstrates good uptake in both small animal and human studies of intracranial malignancies. Future studies on larger numbers of subjects and a wider array of brain tumors are planned. TRIAL REGISTRATION: ClinicalTrials.gov NCT01186601.


Assuntos
Neoplasias Encefálicas/diagnóstico , Ácido Glutâmico/análogos & derivados , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X , Tirosina/análogos & derivados , Adulto , Idoso , Animais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Estudos de Casos e Controles , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Fluordesoxiglucose F18 , Glioblastoma/diagnóstico , Ácido Glutâmico/química , Xenoenxertos , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Ratos , Tomografia Computadorizada por Raios X/métodos , Tirosina/química
18.
J Nucl Med ; 57(6): 900-6, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26823561

RESUMO

UNLABELLED: Training for accurate image interpretation is essential for the clinical use of ß-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 ß-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.


Assuntos
Compostos de Anilina , Processamento de Imagem Assistida por Computador/métodos , Tomografia por Emissão de Pósitrons , Estilbenos , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Sensibilidade e Especificidade
19.
Radiology ; 279(3): 898-905, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26785040

RESUMO

Purpose To evaluate the normal biodistribution and kinetics of (S)-4-(3-[18F]fluoropropyl)-l-glutamic acid ((18)F FSPG) in healthy volunteers and to compare (18)F FSPG mean and maximum standardized uptake values (SUVmean and SUVmax, respectively) with those of (18)F fluorodeoxyglucose (FDG) across a variety of organs. Materials and Methods This protocol was reviewed and approved by all appropriate regulatory authorities. An 8-mCi (±10%) dose of (18)F FSPG was given to five subjects (three women, two men), and seven whole-body positron emission tomography (PET) scans were performed 5, 10, 20, 30, 45, 150, and 240 minutes after injection. Regions of interest were analyzed on the resultant (18)F FSPG images to evaluate the kinetics of this radiotracer. The images obtained 45 minutes after injection were used to measure SUVmean and SUVmax in additional regions of the body. These values were compared with similar values obtained with (18)F FDG PET published previously. Descriptive statistics, including average and standard deviation across the five subjects, were used. (18)F FSPG SUVmean and SUVmax were compared. Results On the (18)F FSPG images obtained 45 minutes after injection, there was only low-grade background activity in the majority of analyzed regions. Prominent activity was seen throughout the pancreas. Clearance of the radiotracer through the kidneys and collection in the bladder also were seen. SUV quantification shows notable differences between (18)F FSPG and (18)F FDG in the pancreas ((18)F FSPG SUVmean, 8.2; (18)F FDG SUVmean, 1.3), stomach ((18)F FSPG SUVmax, 3.6; (18)F FDG SUVmax, 1.6), and brain ((18)F FSPG SUVmean, 0.08; (18)F FDG SUVmean, 7.8). The kinetic data showed rapid clearance of the radiotracer from the blood pool and most organs, except the pancreas. Conclusion (18)F FSPG is a PET radiopharmaceutical characterized by rapid clearance from most healthy tissues, except the pancreas and kidneys. A consistent biodistribution pattern was observed with low background uptake. The physiologic uptake of this new radiotracer throughout the body is described in more detail, which is important for improved interpretative accuracy and understanding potential clinical applications. (©) RSNA, 2016.


Assuntos
Glutamatos/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Feminino , Fluordesoxiglucose F18/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Tomografia por Emissão de Pósitrons
20.
J Nucl Med ; 57(1): 67-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26471694

RESUMO

UNLABELLED: We explored system [Formula: see text] transporter activity and the detection of inflammatory or infectious lesions using (4S)-4-(3-(18)F-fluoropropyl)-l-glutamate ((18)F-FSPG) PET. METHODS: In 10 patients with various inflammatory or infectious diseases, as many as 5 of the largest lesions were selected as reference lesions. (18)F-FSPG images were assessed visually and quantitatively. Expression levels of xCT, CD44, and surface markers of inflammatory cells were evaluated by immunohistochemistry. RESULTS: (18)F-FSPG PET detected all reference lesions. (18)F-FSPG uptake in sarcoidosis was significantly higher than that in nonsarcoidosis. The lesion-to-blood-pool SUV ratio for (18)F-FSPG was comparable to that for (18)F-FDG in sarcoidosis. In nonsarcoidosis, however, it was significantly lower. In 5 patients with available tissue samples, the SUVmax for (18)F-FSPG and CD163 were negatively correlated (ρ = -0.872, P = 0.054). CONCLUSION: (18)F-FSPG PET may detect inflammatory lesions when activated macrophages or monocytes are present, such as in sarcoidosis.


Assuntos
Glutamatos , Infecção/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Glutamatos/metabolismo , Glutamatos/farmacocinética , Humanos , Infecção/metabolismo , Masculino , Pessoa de Meia-Idade , Sarcoidose/diagnóstico por imagem , Sarcoidose/metabolismo , Distribuição Tecidual , Tomografia Computadorizada por Raios X
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