Dataset Information

PET quantification of brain O-GlcNAcase with [18F]LSN3316612 in healthy human volunteers.

ABSTRACT: BACKGROUND:Previous studies found that [18F]LSN3316612 was a promising positron emission tomography (PET) radioligand for imaging O-GlcNAcase in nonhuman primates and human volunteers. This study sought to further evaluate the suitability of [18F]LSN3316612 for human clinical research. METHODS:Kinetic evaluation of [18F]LSN3316612 was conducted in a combined set of baseline brain scans from 17 healthy human volunteers and test-retest imaging was conducted in 10 of these volunteers; another 6 volunteers had whole-body scans to measure radiation exposure to body organs. Total distribution volume (VT) estimates were compared for the one- and two-tissue compartment models with the arterial input function. Test-retest variability and reliability were evaluated via mean difference and intraclass correlation coefficient (ICC). The time stability of VT was assessed down to a 30-min scan time. An alternative quantification method for [18F]LSN3316612 binding without blood was also investigated to assess the possibility of eliminating arterial sampling. RESULTS:Brain uptake was generally high and could be quantified as VT with excellent identifiability using the two-tissue compartment model. [18F]LSN3316612 exhibited good absolute test-retest variability (12.5%), but the arithmetic test-retest variability was far from 0 (11.3%), reflecting a near-uniform increase of VT on the retest scan in nine of 10 volunteers. VT values were stable after 110 min in all brain regions, suggesting that no radiometabolites accumulated in the brain. Measurements obtained using only brain activity (i.e., area under the curve (AUC) from 150-180 min) correlated strongly with regional VT values during test-retest conditions (R2 = 0.84), exhibiting similar reliability to VT (ICC = 0.68 vs. 0.64). Estimated radiation exposure for [18F]LSN3316612 PET was 20.5 ± 2.1 ?Sv/MBq, comparable to other 18F-labeled radioligands for brain imaging. CONCLUSIONS:[18F]LSN3316612 is an excellent PET radioligand for imaging O-GlcNAcase in the human brain. Alternative quantification without blood is possible, at least for within-subject repeat studies. However, the unexplained increase of VT under retest conditions requires further investigation.

SUBMITTER: Lee JH

PROVIDER: S-EPMC7072082 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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PET quantification of brain O-GlcNAcase with [<sup>18</sup>F]LSN3316612 in healthy human volunteers.

Lee Jae-Hoon JH Liow Jeih-San JS Paul Soumen S Morse Cheryl L CL Haskali Mohammad B MB Manly Lester L Shcherbinin Sergey S Ruble J Craig JC Kant Nancy N Collins Emily C EC Nuthall Hugh N HN Zanotti-Fregonara Paolo P Zoghbi Sami S SS Pike Victor W VW Innis Robert B RB

EJNMMI research 20200314 1

<h4>Background</h4>Previous studies found that [<sup>18</sup>F]LSN3316612 was a promising positron emission tomography (PET) radioligand for imaging O-GlcNAcase in nonhuman primates and human volunteers. This study sought to further evaluate the suitability of [<sup>18</sup>F]LSN3316612 for human clinical research.<h4>Methods</h4>Kinetic evaluation of [<sup>18</sup>F]LSN3316612 was conducted in a combined set of baseline brain scans from 17 healthy human volunteers and test-retest imaging was co ...[more]

PMID: 32172476

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Project description:BACKGROUND:Positron emission tomography (PET) is increasingly applied for in vivo brown adipose tissue (BAT) research in healthy volunteers. To limit the radiation exposure, the injected 18F-FDG tracer dose should be as low as possible. With simultaneous PET/MR imaging, the radiation exposure due to computed tomography (CT) can be avoided, but more importantly, the PET acquisition time can often be increased to match the more extensive magnetic resonance (MR) imaging protocol. The potential gain in detected coincidence counts, due to the longer acquisition time, can then be applied to decrease the injected tracer dose. The aim of this study was to investigate the minimal 18F-FDG dose for a 10-min time-of-flight (TOF) PET/MR acquisition that would still allow accurate quantification of supraclavicular BAT volume and activity. METHODS:Twenty datasets from 13 volunteers were retrospectively included from a prospective clinical study. PET emission datasets were modified to simulate step-wise reductions of the original 75?MBq injected dose. The resulting PET images were visually and quantitatively assessed and compared to a 4-min reference scan. For the visual assessment, the image quality and artifacts were scored using a 5-point and a 3-point Likert scale. For the quantitative analysis, image noise and artifacts, BAT metabolic activity, BAT metabolic volume (BMV), and total BAT glycolysis (TBG) were investigated. RESULTS:The visual assessment showed still good image quality for the 35%, 30%, and 25% activity reconstructions with no artifacts. Quantitatively, the background noise was similar to the reference for the 35% and 30% activity reconstructions and the artifacts started to increase significantly in the 25% and lower activity reconstructions. There was no significant difference in supraclavicular BAT metabolic activity, BMV, and TBG between the reference and the 35% to 20% activity reconstructions. CONCLUSIONS:This study indicates that when the PET acquisition time is matched to the 10-min MRI protocol, the injected 18F-FDG tracer dose can be reduced to approximately 19?MBq (25%) while maintaining image quality and accurate supraclavicular BAT quantification. This could decrease the effective dose from 1.4?mSv to 0.36?mSv.

Project description:PURPOSE:Beta-secretase 1 (BACE1) enzyme is implicated in the pathophysiology of Alzheimer's disease. [18F]PF-06684511 is a positron emission tomography (PET) radioligand for imaging BACE1. Despite favorable brain kinetic properties, the effective dose (ED) of [18F]PF-06684511 estimated in non-human primates was relatively high. This study was therefore designed to evaluate the whole-body distribution, dosimetry, quantification, and test-retest reliability of imaging brain BACE1 with [18F]PF-06684511 in healthy volunteers. METHODS:Five subjects were studied for the dosimetry study. Whole-body PET was performed for 366 min with 4 PET-CT sessions. Estimates of the absorbed radiation dose were calculated using the male adult model. Eight subjects participated in the test-retest study. Brain PET measurements were conducted for 123 min with an interval of 5 to 19 days between test and retest conditions. The total distribution volume (VT) was estimated with one-tissue (1T), two-tissue (2T), compartment model (CM), and graphical analysis. Test-retest variability (TRV) and intraclass correlation coefficient (ICC) of VT were calculated as reliability measures. RESULTS:In the dosimetry study, the highest uptake was found in the liver (25.2?±?2.3 %ID at 0.5 h) and the largest dose was observed in the pancreas (92.9?±?52.2 ?Sv/MBq). The calculated ED was 24.7?±?0.8 ?Sv/MBq. In the test-retest study, 2TCM described the time-activity curves well. VT (2TCM) was the highest in the anterior cingulate cortex (6.28?±?1.09 and 6.85?±?0.81) and the lowest in the cerebellum (4.23?±?0.88 and 4.20?±?0.75). Mean TRV and ICC of VT (2TCM) were 16.5% (12.4-20.5%) and 0.496 (0.291-0.644). CONCLUSION:The ED of [18F]PF-06684511 was similar to other 18F radioligands, allowing repeated PET measurements. 2TCM was the most appropriate quantification method. TRV of VT was similar to other radioligands without a reference region, albeit with lower ICC. These data indicated that [18F]PF-06684511 is a suitable radioligand to measure BACE1 level in the human brain. TRIAL REGISTRATION:EudraCT 2016-001110-19 (registered 2016-08-08).

Project description:PURPOSE: Compartmental modelling of 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) PET-derived kinetics provides a method for noninvasive assessment of the proliferation rate of gliomas. Such analyses, however, require an input function generally derived by serial blood sampling and counting. In the current study, 18F-FLT kinetic parameters obtained from image-derived input functions were compared with those from input functions derived from arterialized blood samples. METHODS: Based on the analysis of 11 patients with glioma (WHO grade II-IV) a procedure for the automated extraction of an input function from 18F-FLT brain PET data was derived. The time-activity curve of the volume of interest with the maximum difference in 18F-FLT uptake during the first 5 min after injection and the period from 60 to 90 min was corrected for partial-volume effects and in vivo metabolism of 18F-FLT. For each patient a two-compartment kinetic model was applied to the tumour tissue using the image-derived input function. The resulting kinetic rate constants K1 (transport across the blood-brain barrier) and Ki (metabolic rate constant or net influx constant) were compared with those obtained from the same data using the input function derived from blood samples. Additionally, the metabolic rate constant was correlated with the frequency of tumour cells stained with Ki-67, a widely used immunohistochemical marker of cell proliferation. RESULTS: The rate constants from kinetic modelling were comparable when the blood sample-derived input functions were replaced by the image-derived functions (K1,img and K1,sample, r = 0.95, p < 10(-5); Ki,img and Ki,sample, r = 0.86, p < 0.001). A paired t-test showed no significant differences in the parameters derived with the two methods (K1,img and K1,sample, p = 0.20; Ki,img and Ki,sample, p = 0.92). Furthermore, a significant correlation between Ki,img and the percentage of Ki-67-positive cells was observed (r = 0.73, p = 0.01). CONCLUSION: Kinetic modelling of 18F-FLT brain PET data using image-derived input functions extracted from human brain PET data with the practical procedure described here provides information about the proliferative activity of brain tumours which might have clinical relevance especially for monitoring of therapy response in future clinical trials.

Project description:UNLABELLED:(18)F-CP-18, or (18S,21S,24S,27S,30S)-27-(2-carboxyethyl)-21-(carboxymethyl)-30-((2S,3R,4R,5R,6S)-6-((2-(4-(3-F18-fluoropropyl)-1H-1,2,3-triazol-1-yl)acetamido)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxamido)-24-isopropyl-18-methyl-17,20,23,26,29-pentaoxo-4,7,10,13-tetraoxa-16,19,22,25,28-pentaazadotriacontane-1,32-dioic acid, is being evaluated as a tissue apoptosis marker for PET imaging. The purpose of this study was to determine the biodistribution and estimate the normal-organ radiation-absorbed doses and effective dose from (18)F-CP-18. METHODS:Successive whole-body PET/CT scans were obtained at approximately 7, 45, 90, 130, and 170 min after intravenous injection of (18)F-CP-18 in 7 healthy human volunteers. Blood samples and urine were collected between the PET/CT scans, and the biostability of (18)F-CP-18 was assessed using high-performance liquid chromatography. The PET scans were analyzed to determine the radiotracer uptake in different organs. OLINDA/EXM software was used to calculate human radiation doses based on the biodistribution of the tracer. RESULTS:(18)F-CP-18 was 54% intact in human blood at 135 min after injection. The tracer cleared rapidly from the blood pool with a half-life of approximately 30 min. Relatively high (18)F-CP-18 uptake was observed in the kidneys and bladder, with diffuse uptake in the liver and heart. The mean standardized uptake values (SUVs) in the bladder, kidneys, heart, and liver at around 50 min after injection were approximately 65, 6, 1.5, and 1.5, respectively. The calculated effective dose was 38 ± 4 ?Sv/MBq, with the urinary bladder wall having the highest absorbed dose at 536 ± 61 ?Gy/MBq using a 4.8-h bladder-voiding interval for the male phantom. For a 1-h voiding interval, these doses were reduced to 15 ± 2 ?Sv/MBq and 142 ± 15 ?Gy/MBq, respectively. For a typical injected activity of 555 MBq, the effective dose would be 21.1 ± 2.2 mSv for the 4.8-h interval, reduced to 8.3 ± 1.1 mSv for the 1-h interval. CONCLUSION:(18)F-CP-18 cleared rapidly through the renal system. The urinary bladder wall received the highest radiation dose and was deemed the critical organ. Both the effective dose and the bladder dose can be reduced by frequent voiding. From the radiation dosimetry perspective, the apoptosis imaging agent (18)F-CP-18 is suitable for human use.

Project description:Unlabelled(18)F-FP-(+)-DTBZ is a novel PET radiotracer targeting vesicular monoamine transporter type 2 (VMAT2). The goal was to explore the image features in normal human brains with (18)F-FP-(+)-DTBZ as a reference of molecular landmark for clinical diagnosis in Parkinson's disease (PD) and related disorders.Materials and methodsA total of 22 healthy subjects (59.3±6.0 years old) including 7 men and 15 women were recruited for MRI and (18)F-FP-(+)-DTBZ PET scans. A total number of 55 brain VOIs were selected for quantitation analysis. The regional specific uptake ratio (SUR) was calculated with occipital as reference from MRI-based spatially normalized (18)F-FP-(+)-DTBZ images. Regional percentage SUR to that of anterior putamen was calculated. Average SUR images were displayed in 2D and 3D space to illustrate the image patterns. The correlation between age and regional VMAT2 uptake was also examined.ResultsVisual assessment showed symmetric uptake of (18)F-FP-(+)-DTBZ and obviously highest in striatum, followed by nucleus accumbens, hypothalamus, substantia nigra, and raphe nuclei. Quantification analysis revealed striatal VMAT2 density of anterior putamen>posterior putamen>caudate nucleus. Other subcortical regions were with moderate VMAT2 distribution (6∼51% SUR of anterior putamen), while slightly lower VMAT2 was observed in cerebellum (10.60% SUR) and much lower in neocortex (<5% SUR). No significant correlation of SUR to age was found in subcortical regions.ConclusionUsing (18)F-FP-(+)-DTBZ PET, we showed the 2D and 3D imaging features of the VMAT2 distribution in vivo in healthy aging brains. The in vivo imaging characteristics of VMAT2 is consistent with the expression of VMAT2 in a recent autopsy study. Therefore, 3D visualization and higher image quality of (18)F-FP-(+)-DTBZ PET imaging might potentially be a powerful biomarker in detecting VMAT2 distribution of subcortical regions, and for Parkinson's disease and related neuropsychiatric disorders involving related monoaminergic systems.

Dataset Information

PET quantification of brain O-GlcNAcase with [18F]LSN3316612 in healthy human volunteers.

Publications

PET quantification of brain O-GlcNAcase with [<sup>18</sup>F]LSN3316612 in healthy human volunteers.

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