PET ligands [18F]LSN3316612 and [11C]LSN3316612 quantify O-linked-β-N-acetyl-glucosamine hydrolase in the brain.
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SUBMITTER: Lu S
PROVIDER: S-EPMC8494060 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeSoluble epoxide hydrolase (sEH) is a promising candidate positron emission tomography (PET) imaging biomarker altered in various disorders, including vascular cognitive impairment (VCI), Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and depression, known to regulate levels of epoxyeicosatrienoic acids (EETs) and play an important role in neurovascular coupling. [18F]FNDP, a PET radiotracer for imaging sEH, was evaluated through quantitative PET imaging in the baboon brain, radiometabolite analysis, and radiation dosimetry estimate.MethodsBaboon [18F]FNDP dynamic PET studies were performed at baseline and with blocking doses of the selective sEH inhibitor AR-9281 to evaluate sEH binding specificity. Radiometabolites of [18F]FNDP in mice and baboons were measured by high-performance liquid chromatography. Regional brain distribution volume (VT) of [18F]FNDP was computed from PET using radiometabolite-corrected arterial input functions. Full body distribution of [18F]FNDP was studied in CD-1 mice, and the human effective dose was estimated using OLINDA/EXM software.Results[18F]FNDP exhibited high and rapid brain uptake in baboons. AR-9281 blocked [18F]FNDP uptake dose-dependently with a baseline VT of 10.9 ± 2.4 mL/mL and a high-dose blocking VT of 1.0 ± 0.09 mL/mL, indicating substantial binding specificity (91.70 ± 1.74%). The VND was estimated as 0.865 ± 0.066 mL/mL. The estimated occupancy values of AR-9281 were 99.2 ± 1.1% for 1 mg/kg, 88.6 ± 1.3% for 0.1 mg/kg, and 33.8 ± 3.8% for 0.02 mg/kg. Murine biodistribution of [18F]FNDP enabled an effective dose estimate for humans (0.032 mSv/MBq). [18F]FNDP forms hydrophilic radiometabolites in murine and non-human primate plasma. However, only minute amounts of the radiometabolites entered the animal brain (< 2% in mice).Conclusions[18F]FNDP is a highly sEH-specific radiotracer that is suitable for quantitative PET imaging in the baboon brain. [18F]FNDP holds promise for translation to human subjects.
| S-EPMC7310027 | biostudies-literature
Project description:Tau aggregates and amyloid-? (A?) plaques are key histopathologic features in Alzheimer disease (AD) and are considered targets for therapeutic intervention as well as biomarkers for diagnostic in vivo imaging agents. This article describes the preclinical in vitro and in vivo characterization of 3 novel compounds-RO6958948, RO6931643, and RO6924963-that bind specifically to tau aggregates and have the potential to become PET tracers for future human use. Methods: RO6958948, RO6931643, and RO6924963 were identified as high-affinity competitors at the 3H-T808 binding site on native tau aggregates in human late-stage AD brain tissue. Binding of tritiated compounds to brain tissue sections of AD patients and healthy controls was analyzed by macro- and microautoradiography and by costaining of tau aggregates and A? plaques on the same tissue section using specific antibodies. All 3 tracer candidates were radiolabeled with a PET nuclide and tested in vivo in tau-naïve baboons to assess brain uptake, distribution, clearance, and metabolism. Results:3H-RO6958948, 3H-RO6931643, and 3H-RO6924963 bound with high affinity and specificity to tau aggregates, clearly lacking affinity for concomitant A? plaques in human AD Braak V tissue sections. The specificity of all 3 radioligands for tau aggregates was supported, first, by binding patterns in AD sections comparable to the tau-specific radioligand 3H-T808; second, by very low nonspecific binding in brain tissue devoid of tau pathology, excluding significant radioligand binding to any other central nervous system target; and third, by macroscopic and microscopic colocalization and quantitative correlation of radioligand binding and tau antibody staining on the same tissue section. RO6958948, RO6931643, and RO6924963 were successfully radiolabeled with a PET nuclide at high specific activity, radiochemical purity, and yield. After intravenous administration of 18F-RO6958948, 11C-RO6931643, and 11C-RO6924963 to baboons, PET scans indicated good brain entry, rapid washout, and a favorable metabolism pattern. Conclusion:18F-RO6958948, 11C-RO6931643, and 11C-RO6924963 are promising PET tracers for visualization of tau aggregates in AD. Head-to-head comparison and validation of these tracer candidates in AD patients and healthy controls will be reported in due course.
| S-EPMC5932750 | biostudies-literature
Project description:PurposeThis study assessed whether the newly developed PET radioligand [11C]PS13, which has shown excellent in vivo selectivity in previous animal studies, could be used to quantify constitutive levels of cyclooxygenase-1 (COX-1) in healthy human brain.MethodsBrain test-retest scans with concurrent arterial blood samples were obtained in 10 healthy individuals. The one- and unconstrained two-tissue compartment models, as well as the Logan graphical analysis were compared, and test-retest reliability and time-stability of total distribution volume (VT) were assessed. Correlation analyses were conducted between brain regional VT and COX-1 transcript levels provided in the Allen Human Brain Atlas.ResultsIn the brain, [11C]PS13 showed highest uptake in the hippocampus and occipital cortex. The pericentral cortex also showed relatively higher uptake compared with adjacent neocortices. The two-tissue compartment model showed the best fit in all the brain regions, and the results from the Logan graphical analysis were consistent with those from the two-tissue compartment model. VT values showed excellent test-retest variability (range 6.0-8.5%) and good reliability (intraclass correlation coefficient range 0.74-0.87). VT values also showed excellent time-stability in all brain regions, confirming that there was no radiometabolite accumulation and that shorter scans were still able to reliably measure VT. Significant correlation was observed between VT and COX-1 transcript levels (r = 0.82, P = 0.007), indicating that [11C]PS13 binding reflects actual COX-1 density in the human brain.ConclusionsThese results from the first-in-human evaluation of the ability of [11C]PS13 to image COX-1 in the brain justifies extending the study to disease populations with neuroinflammation.Clinical trial registrationNCT03324646 at https://clinicaltrials.gov/ . Registered October 30, 2017. Retrospectively registered.
| S-EPMC8261645 | biostudies-literature
Project description:Three oligothiophenes were evaluated as PET ligands for the study of local and systemic amyloidosis ex vivo using tissue from patients with amyloid deposits and in vivo using healthy animals and PET-CT. The ex vivo binding studies revealed that all three labeled compounds bound specifically to human amyloid deposits. Specific binding was found in the heart, kidney, liver, and spleen. To verify the specificity of the oligothiophenes toward amyloid deposits, tissue sections with amyloid pathology were stained using the fluorescence exhibited by the compounds and evaluated with multiphoton microscopy. Furthermore, a in vivo monkey PET-CT study showed very low uptake in the brain, pancreas, and heart of the healthy animal indicating low nonspecific binding to healthy tissue. The biological evaluations indicated that this is a promising group of compounds for the visualization of systemic and localized amyloidosis.
| S-EPMC4834648 | biostudies-literature
Project description:ObjectiveThe tumour-to-normal ratio (T/N) is a representative index reflecting brain tumour activity by 18F-fluorodeoxyglucose (FDG) and 11C-methionine (MET) PET. We proposed a new automated method of calculating the normal reference value (N-value) for use as the denomination of T/N. This method uses voxel-based analysis of FDG- and MET-PET images. We compared the results of this method with those of the standard region-of-interest (ROI) method.MethodsData sets were obtained from 32 patients with newly diagnosed glioma and 13 patients with recurrent brain tumour. Our methods were as follows: (1) FDG-PET and MET-PET images were co-registered. (2) The areas where the FDG uptake was higher than a set threshold were selected. (3) For the corresponding areas of MET-PET images, mode and mean voxel values were calculated as tentative MET N-values. (4) Applying the same coordinates to FDG-PET, the voxel values were averaged and used as tentative FDG N-values. (5) The threshold of FDG-PET and whether to use the mode or the mean voxel values were computationally optimized using learning data sets. (6) Applying the optimal threshold and either the mode or mean, N-values of FDG and MET were finally determined.ResultsN-values determined by our automated method showed excellent agreement with those determined by a manual ROI method (ICC(2,1) > 0.78). These values were significantly correlated with mean manual N-values (p < 0.001).ConclusionsOur new method shows sufficiently good agreement with the standard method and can provide a more objective metabolic index.
| S-EPMC5352759 | biostudies-literature
Project description:PurposeThe aim of our study was to investigate the efficacy of 18F-Fluciclovine brain PET imaging in recurrent gliomas, and to compare the utility of these images to that of contrast enhanced magnetic resonance imaging (MRI) and to [11C-methyl]-L-methionine (11C-Methionine) PET imaging. We also sought to gain insight into the factors affecting the uptake of 18F-FACBC in both tumors and normal brain, and specifically to evaluate how the uptake in these tissues varied over an extended period of time post injection.MethodsTwenty-seven patients with recurrent or progressive primary brain tumor (based on clinical and MRI/CT data) were studied using dynamic 18F-Fluciclovine brain imaging for up to 4 h. Of these, 16 patients also had 11C-Methionine brain scans. Visual findings, semi-quantitative analyses and pharmacokinetic modeling of a subset of the 18F-Fluciclovine images was conducted. The information derived from these analyses were compared to data from 11C-Methionine and to contrast-enhanced MRI.Results18F-Fluciclovine was positive for all 27 patients, whereas contrast MRI was indeterminate for three patients. Tumor 18F-Fluciclovine SUVmax ranged from 1.5 to 10.5 (average: 4.5?±?2.3), while 11C-Methionine's tumor SUVmax ranged from 2.2 to 10.2 (average: 5.0?±?2.2). Image contrast was higher with 18F-Fluciclovine compared to 11C-Methionine (p?<?0.0001). This was due to 18F-Fluciclovine's lower background in normal brain tissue (0.5?±?0.2 compared to 1.3?±?0.4 for 11C-Methionine). 18F-Fluciclovine uptake in both normal brain and tumors was well described by a simple one-compartment (three-parameter: Vb,k1,k2) model. Normal brain was found to approach transient equilibrium with a half-time that varied greatly, ranging from 1.5 to 8.3 h (mean 2.7?±?2.3 h), and achieving a consistent final distribution volume averaging 1.4?±?0.2 ml/cc. Tumors equilibrated more rapidly (t1/2ranging from 4 to 148 min, average 57?±?51 min), with an average distribution volume of 3.2?±?1.1 ml/cc. A qualitative comparison showed that the rate of normal brain uptake of 11C-Methionine was much faster than that of 18F-Fluciclovine.ConclusionTumor uptake of 18F-Fluciclovine correlated well with the established brain tumor imaging agent 11C-Methionine but provided significantly higher image contrast. 18F-Fluciclovine may be particularly useful when the contrast MRI is non-diagnostic. Based on the data gathered, we were unable to determine whether Fluciclovine uptake was due solely to recurrent tumor or if inflammation or other processes also contributed.
| S-EPMC7188736 | biostudies-literature
Project description:The primary aim of the study was to evaluate the role of [18F]Fluciclovine PET/CT in the characterization of intra-prostatic lesions in high-risk primary PCa patients eligible for radical prostatectomy, in comparison with conventional [11C]Choline PET/CT and validated by prostatectomy pathologic examination. Secondary aims were to determine the performance of PET semi-quantitative parameters (SUVmax; target-to-background ratios [TBRs], using abdominal aorta, bone marrow and liver as backgrounds) for malignant lesion detection (and best cut-off values) and to search predictive factors of malignancy. A six sextants prostate template was created and used by PET readers and pathologists for data comparison and validation. PET visual and semi-quantitative analyses were performed: for instance, patient-based, blinded to histopathology; subsequently lesion-based, un-blinded, according to the pathology reference template. Among 19 patients included (mean age 63 years, 89% high and 11% very-high-risk, mean PSA 9.15 ng/mL), 45 malignant and 31 benign lesions were found and 19 healthy areas were selected (n = 95). For both tracers, the location of the "blinded" prostate SUVmax matched with the lobe of the lesion with the highest pGS in 17/19 cases (89%). There was direct correlation between [18F]Fluciclovine uptake values and pISUP. Overall, lesion-based (n = 95), the performance of PET semiquantitative parameters, with either [18F]Fluciclovine or [11C]Choline, in detecting either malignant/ISUP2-5/ISUP4-5 PCa lesions, was moderate and similar (AUCs ≥ 0.70) but still inadequate (AUCs ≤ 0.81) as a standalone staging procedure. A [18F]Fluciclovine TBR-L3 ≥ 1.5 would depict a clinical significant lesion with a sensitivity and specificity of 85% and 68% respectively; whereas a SUVmax cut-off value of 4 would be able to identify a ISUP 4-5 lesion in all cases (sensitivity 100%), although with low specificity (52%). TBRs (especially with threshold significantly higher than aorta and slightly higher than bone marrow), may be complementary to implement malignancy targeting.
| S-EPMC8037300 | biostudies-literature
Project description:[18F]Flortaucipir is a PET tau tracer used to visualize tau binding in Alzheimer's disease (AD) in vivo. The present study evaluated the performance of several methods to obtain parametric images of [18F]flortaucipir. One hundred and thirty minutes dynamic PET scans were performed in 10 AD patients and 10 controls. Parametric images were generated using different linearization and basis function approaches. Regional binding potential (BPND) and volume of distribution (VT) values obtained from the parametric images were compared with corresponding values derived using the reversible two-tissue compartment model (2T4k_VB). Performance of SUVr parametric images was assessed by comparing values with distribution volume ratio (DVR) and SRTM-derived BPND estimates obtained using non-linear regression (NLR). Spectral analysis (SA) (r2 = 0.92; slope = 0.99) derived VT correlated well with NLR-derived VT. RPM (r2 = 0.95; slope = 0.98) derived BPND correlated well with NLR-derived DVR. Although SUVr80-100 min correlated well with NLR-derived DVR (r2 = 0.91; slope = 1.09), bias in SUVr appeared to depend on uptake time and underlying level of specific binding. In conclusion, RPM and SA provide parametric images comparable to the NLR estimates. Individual SUVr values are biased compared with DVR and this bias requires further study in a larger dataset in order to understand its consequences.
| S-EPMC7044757 | biostudies-literature
Project description:Knowledge of the within-subject variability of 18F-FDG PET/MRI measurements is necessary for proper interpretation of quantitative PET or MRI metrics in the context of therapeutic efficacy assessments with integrated PET/MRI scanners. The goal of this study was to determine the test-retest repeatability of these metrics on PET/MRI, with comparison to similar metrics acquired by PET/CT. Methods: This prospective study enrolled subjects with pathology-proven pelvic malignancies. Baseline imaging consisted of PET/CT immediately followed by PET/MRI, using a single 370-MBq 18F-FDG dose. Repeat imaging was performed within 7 d using an identical imaging protocol, with no oncologic therapy between sessions. PET imaging on both scanners consisted of a list-mode acquisition at a single pelvic station. The MRI consisted of 2-point Dixon imaging for attenuation correction, standard sequences for anatomic correlation, and diffusion-weighted imaging. PET data were statically reconstructed using various frame durations and minimizing uptake time differences between sessions. SUV metrics were extracted for both PET/CT and PET/MRI in each imaging session. Apparent diffusion coefficient (ADC) metrics were extracted for both PET/MRI sessions. Results: The study cohort consisted of 14 subjects (13 female, 1 male) with various pelvic cancers (11 cervical, 2 rectal, 1 endometrial). For SUVmax, the within-subject coefficient of variation (wCV) appeared higher for PET/CT (8.5%-12.8%) than PET/MRI (6.6%-8.7%) across all PET reconstructions, though with no significant repeatability differences (all P values ≥ 0.08) between modalities. For lean body mass-adjusted SUVpeak, the wCVs appeared similar for PET/CT (9.9%-11.5%) and PET/MRI (9.2%-11.3%) across all PET reconstructions, again with no significant repeatability differences (all P values ≥ 0.14) between modalities. For PET/MRI, the wCV for ADCmedian of 3.5% appeared lower than the wCVs for SUVmax (6.6%-8.7%) and SULpeak (9.2%-11.3%), though without significant repeatability differences (all P values ≥ 0.23). Conclusion: For solid tumors of the pelvis, the repeatability of the evaluated SUV and ADC metrics on 18F-FDG PET/MRI is both acceptably high and similar to previously published values for 18F-FDG PET/CT and MRI, supporting the use of 18F-FDG PET/MRI for quantitative oncologic treatment response assessments.
| S-EPMC6681694 | biostudies-literature
Project description:Positron emission tomography (PET) imaging is used to localize recurrent disease in prostate cancer (PCa). The tracer 68Ga-PSMA-11 visualizes lesions overexpressing prostate-specific membrane antigen (PSMA), while 11C-acetate visualizes lesions with increased anabolic metabolism. The aim of this study was to compare the performance of PSMA-PET and acetate-PET in re-staging patients with biochemical relapse. Thirty PCa patients with prostate-specific antigen (PSA) relapse after primary curative therapy were prospectively evaluated. PET/CT examinations using 11C-acetate and 68Ga-PSMA-11 were performed. Identified lesions were categorized according to anatomical location and PET measurements were correlated with PSA at time of scan. Tumour lesions showed higher semi-quantitative uptake values on PSMA-PET than acetate-PET. PSMA-PET identified more lesions in 11 patients, fewer lesions in eight patients, and identical number of lesions in 11 patients. This study indicates better diagnostic performance of PSMA-PET, particularly in detecting lymph node (81% vs 60%, p = 0.02) and bone metastasis (95% vs 61%, p = 0.0001) compared to acetate-PET. However, 38% of PSMA-expressing metastases appear to be metabolically inactive and 15% of metabolically active metastases lack PSMA expression. Addition of PET with a metabolic tracer, such as 11C-acetate, might be beneficial before making treatment decisions.
| S-EPMC7081247 | biostudies-literature