Neuroinflammation Parallels 18F-PI-2620 Positron Emission Tomography Patterns in Primary 4-Repeat Tauopathies.

BACKGROUND: Preclinical, postmortem, and positron emission tomography (PET) imaging studies have pointed to neuroinflammation as a key pathophysiological hallmark in primary 4-repeat (4R) tauopathies and its role in accelerating disease progression. OBJECTIVE: We tested whether microglial activation (1) progresses in similar spatial patterns as the primary pathology tau spreads across interconnected brain regions, and (2) whether the degree of microglial activation parallels tau pathology spreading. METHODS: We examined in vivo associations between tau aggregation and microglial activation in 31 patients with clinically diagnosed 4R tauopathies, using 18F-PI-2620 PET and 18F-GE180 (translocator protein [TSPO]) PET. We determined tau epicenters, defined as subcortical brain regions with highest tau PET signal, and assessed the connectivity of tau epicenters to cortical regions of interest using a 3-T resting-state functional magnetic resonance imaging template derived from age-matched healthy elderly controls. RESULTS: In 4R tauopathy patients, we found that higher regional tau PET covaries with elevated TSPO-PET across brain regions that are functionally connected to each other (ß = 0.414, P < 0.001). Microglial activation follows similar distribution patterns as tau and distributes primarily across brain regions strongly connected to patient-specific tau epicenters (ß = -0.594, P < 0.001). In these regions, microglial activation spatially parallels tau distribution detectable with 18F-PI-2620 PET. CONCLUSIONS: Our findings indicate that the spatial expansion of microglial activation parallels tau distribution across brain regions that are functionally connected to each other, suggesting that tau and inflammation are closely interrelated in patients with 4R tauopathies. The combination of in vivo tau and inflammatory biomarkers could therefore support the development of immunomodulatory strategies for disease-modifying treatments in these conditions. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Clinical [18F]FSPG Positron Emission Tomography Imaging Reveals Heterogeneity in Tumor-Associated System xc- Activity.

BACKGROUND: (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) positron emission tomography/computed tomography (PET/CT) provides a readout of system xc- transport activity and has been used for cancer detection in clinical studies of different cancer types. As system xc- provides the rate-limiting precursor for glutathione biosynthesis, an abundant antioxidant, [18F]FSPG imaging may additionally provide important prognostic information. Here, we performed an analysis of [18F]FSPG radiotracer distribution between primary tumors, metastases, and normal organs from cancer patients. We further assessed the heterogeneity of [18F]FSPG retention between cancer types, and between and within individuals. METHODS: This retrospective analysis of prospectively collected data compared [18F]FSPG PET/CT in subjects with head and neck squamous cell cancer (HNSCC, n = 5) and non-small-cell lung cancer (NSCLC, n = 10), scanned at different institutions. Using semi-automated regions of interest drawn around tumors and metastases, the maximum standardized uptake value (SUVmax), SUVmean, SUV standard deviation and SUVpeak were measured. [18F]FSPG time-activity curves (TACs) for normal organs, primary tumors and metastases were subsequently compared to 18F-2-fluoro-2-deoxy-D-glucose ([18F]FDG) PET/CT at 60 min post injection (p.i.). RESULTS: The mean administered activity of [18F]FSPG was 309.3 ± 9.1 MBq in subjects with NSCLC and 285.1 ± 11.3 MBq in those with HNSCC. The biodistribution of [18F]FSPG in both cohorts showed similar TACs in healthy organs from cancer patients. There was no statistically significant overall difference in the average SUVmax of tumor lesions at 60 min p.i. for NSCLC (8.1 ± 7.1) compared to HNSCC (6.0 ± 4.1; p = 0.29) for [18F]FSPG. However, there was heterogeneous retention between and within cancer types; the SUVmax at 60 min p.i. ranged from 1.4 to 23.7 in NSCLC and 3.1-12.1 in HNSCC. CONCLUSION: [18F]FSPG PET/CT imaging from both NSCLC and HNSCC cohorts showed the same normal-tissue biodistribution, but marked tumor heterogeneity across subjects and between lesions. Despite rapid elimination through the urinary tract and low normal-background tissue retention, the diagnostic potential of [18F]FSPG was limited by variability in tumor retention. As [18F]FSPG retention is mediated by the tumor's antioxidant capacity and response to oxidative stress, this heterogeneity may provide important insights into an individual tumor's response or resistance to therapy.

Increased off-target binding of [18F]florbetaben in the skull of women with reduced skull density.

AIM: To investigate the relationship between off-target binding of the amyloid tracer [18F]florbetaben (FBB) in the skull and skull density. METHODS: Forty-three consecutive patients were included retrospectively (age 70.2±7.5y, 42% females, 65% amyloid-positive). For each patient, CT skull density (in Hounsfield units) and (late) FBB uptake in the skull were obtained using an individual skull mask generated by warping the skull tissue probability map provided by the statistical parametric mapping software package (version SPM12) to the native patient space. Skull FBB uptake (mean of the 10% hottest voxels) was scaled to the individual median FBB uptake in the pons. The association between skull FBB uptake and skull density was tested by correlation analyses. Univariate analysis of variance (ANOVA) of skull FBB uptake with dichotomized skull density (low: ≤ median, high), sex (female, male) and amyloid-status (positive, negative) as between-subjects factors was used to assess the impact of sex and amyloid status. RESULTS: There was a significant inverse correlation between skull FBB uptake and skull density (Pearson correlation coefficient -0.518, p < 0.001; Spearman rho -0.321, p = 0.036). The ANOVA confirmed the bone density effect on the FBB uptake in the skull (p = 0.019). In addition, sex (p = 0.012) and density*sex interaction (p = 0.016) had a significant impact. Skull FBB uptake was significantly higher in females with low skull density than for all other combinations of sex and skull density. Amyloid status did not reach statistical significance (p = 0.092). CONCLUSION: Off-target binding of FBB in the skull is inversely associated with skull density. The relationship is mainly driven by females. Amyloid status does not have a major impact on skull FBB binding.

Noninvasive In Vivo Thrombus Imaging in Patients With Ischemic Stroke or Transient Ischemic Attack-Brief Report.

BACKGROUND: 18F-GP1 is a novel positron-emitting radiotracer that is highly specific for activated platelets and thrombus. In a proof-of-concept study, we aimed to determine its potential clinical application in establishing the role and origin of thrombus in ischemic stroke. METHODS: Eleven patients with recent ischemic stroke (n=9) or transient ischemic attack (n=2) underwent 18F-GP1 positron emission tomography and computed tomography angiography at a median of 11 (range, 2-21) days from symptom onset. 18F-GP1 uptake (maximum target-to-background ratio) was assessed in the carotid arteries and brain. RESULTS: 18F-GP1 uptake was identified in 10 of 11 patients: 4 in the carotid arteries only, 3 in the brain only, and 3 in both the brain and carotid arteries. In those with carotid uptake, 4 participants had >50% stenosis and 3 had nonstenotic disease. One case had bilateral stenotic disease (>70%), but only the culprit carotid artery demonstrated 18F-GP1 uptake. The average uptake was higher in the culprit (median maximum target-to-background ratio, 1.55 [interquartile range, 1.26-1.82]) compared with the contralateral nonculprit carotid artery (maximum target-to-background ratio, 1.22 [1.19-1.6]). In those with brain 18F-GP1 uptake (maximum target-to-background ratio, 6.45 [4.89-7.65]), areas of acute infarction on computed tomography correlated with brain 18F-GP1 uptake in 6 cases. Ex vivo autoradiography of postmortem infarcted brain tissue showed focal uptake corresponding to intraluminal thrombus within the culprit vessel and downstream microvasculature. There was also evidence of diffuse uptake within some of the infarcted brain tissue reflecting parenchymal petechial hemorrhage. CONCLUSIONS: 18F-GP1 positron emission tomography and computed tomography angiography is a novel noninvasive method of identifying in vivo cerebrovascular thrombosis, which holds major promise in understanding the role and origin of thrombosis in stroke. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03943966.

Validation of quantitative assessment of florbetaben PET scans as an adjunct to the visual assessment across 15 software methods.

PURPOSE: Amyloid positron emission tomography (PET) with [18F]florbetaben (FBB) is an established tool for detecting Aß deposition in the brain in vivo based on visual assessment of PET scans. Quantitative measures are commonly used in the research context and allow continuous measurement of amyloid burden. The aim of this study was to demonstrate the robustness of FBB PET quantification. METHODS: This is a retrospective analysis of FBB PET images from 589 subjects. PET scans were quantified with 15 analytical methods using nine software packages (MIMneuro, Hermes BRASS, Neurocloud, Neurology Toolkit, statistical parametric mapping (SPM8), PMOD Neuro, CapAIBL, non-negative matrix factorization (NMF), AmyloidIQ) that used several metrics to estimate Aß load (SUVR, centiloid, amyloid load, and amyloid index). Six analytical methods reported centiloid (MIMneuro, standard centiloid, Neurology Toolkit, SPM8 (PET only), CapAIBL, NMF). All results were quality controlled. RESULTS: The mean sensitivity, specificity, and accuracy were 96.1 ± 1.6%, 96.9 ± 1.0%, and 96.4 ± 1.1%, respectively, for all quantitative methods tested when compared to histopathology, where available. The mean percentage of agreement between binary quantitative assessment across all 15 methods and visual majority assessment was 92.4 ± 1.5%. Assessments of reliability, correlation analyses, and comparisons across software packages showed excellent performance and consistent results between analytical methods. CONCLUSION: This study demonstrated that quantitative methods using both CE marked software and other widely available processing tools provided comparable results to visual assessments of FBB PET scans. Software quantification methods, such as centiloid analysis, can complement visual assessment of FBB PET images and could be used in the future for identification of early amyloid deposition, monitoring disease progression and treatment effectiveness.

[18F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data.

OBJECTIVES: Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer`s disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions. METHODS: A cross-sectional cohort of 24 transgenic (PS2APP) and 25 wild-type mice (age range: 4.3-21.0 months) underwent 60 min dynamic [18F]fluorodeprenyl-D2 ([18F]F-DED), static 18 kDa translocator protein (TSPO, [18F]GE-180) and ß-amyloid ([18F]florbetaben) PET imaging. Quantification was performed via image derived input function (IDIF, cardiac input), simplified non-invasive reference tissue modelling (SRTM2, DVR) and late-phase standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analyses of glial fibrillary acidic protein (GFAP) and MAO-B were performed to validate PET imaging by gold standard assessments. Patients belonging to the Alzheimer's disease continuum (AD, n = 2), Parkinson's disease (PD, n = 2), multiple system atrophy (MSA, n = 2), autoimmune encephalitis (n = 1), oligodendroglioma (n = 1) and one healthy control underwent 60 min dynamic [18F]F-DED PET and the data were analyzed using equivalent quantification strategies. RESULTS: We selected the cerebellum as a pseudo-reference region based on the immunohistochemical comparison of age-matched PS2APP and WT mice. Subsequent PET imaging revealed that PS2APP mice showed elevated hippocampal and thalamic [18F]F-DED DVR when compared to age-matched WT mice at 5 months (thalamus: + 4.3%; p = 0.048), 13 months (hippocampus: + 7.6%, p = 0.022) and 19 months (hippocampus: + 12.3%, p < 0.0001; thalamus: + 15.2%, p < 0.0001). Specific [18F]F-DED DVR increases of PS2APP mice occurred earlier when compared to signal alterations in TSPO and ß-amyloid PET and [18F]F-DED DVR correlated with quantitative immunohistochemistry (hippocampus: R = 0.720, p < 0.001; thalamus: R = 0.727, p = 0.002). Preliminary experience in patients showed [18F]F-DED VT and SUVr patterns, matching the expected topology of reactive astrogliosis in neurodegenerative (MSA) and neuroinflammatory conditions, whereas the patient with oligodendroglioma and the healthy control indicated [18F]F-DED binding following the known physiological MAO-B expression in brain. CONCLUSIONS: [18F]F-DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases.

Noninvasive In Vivo Coronary Artery Thrombus Imaging.

BACKGROUND: The diagnosis and management of myocardial infarction are increasingly complex, and establishing the presence of intracoronary thrombosis has major implications for both the classification and treatment of myocardial infarction. OBJECTIVES: The aim of this study was to investigate whether positron emission tomographic (PET) and computed tomographic (CT) imaging could noninvasively detect in vivo thrombus formation in human coronary arteries using a novel glycoprotein IIb/IIIa receptor antagonist-based radiotracer, 18F-GP1. METHODS: In a single-center observational case-control study, patients with or without acute myocardial infarction underwent coronary 18F-GP1 PET/CT angiography. Coronary artery 18F-GP1 uptake was assessed visually and quantified using maximum target-to-background ratios. RESULTS: 18F-GP1 PET/CT angiography was performed in 49 patients with and 50 patients without acute myocardial infarction (mean age: 61 ± 9 years, 75% men). Coronary 18F-GP1 uptake was apparent in 39 of the 49 culprit lesions (80%) in patients with acute myocardial infarction. False negative results appeared to relate to time delays to scan performance and low thrombus burden in small-caliber distal arteries. On multivariable regression analysis, culprit vessel status was the only independent variable associated with higher 18F-GP1 uptake. Extracoronary cardiac 18F-GP1 findings included a high frequency of infarct-related intramyocardial uptake (35%) as well as left ventricular (8%) or left atrial (2%) thrombus. CONCLUSIONS: Coronary 18F-GP1 PET/CT angiography is the first noninvasive selective technique to identify in vivo coronary thrombosis in patients with acute myocardial infarction. This novel approach can further define the role and location of thrombosis within the heart and has the potential to inform the diagnosis, management, and treatment of patients with acute myocardial infarction. (In-Vivo Thrombus Imaging With 18F-GP1, a Novel Platelet PET Radiotracer [iThrombus]; NCT03943966).

Evaluation of tau deposition using 18F-PI-2620 PET in MCI and early AD subjects-a MissionAD tau sub-study.

BACKGROUND: The ability of 18F-PI-2620 PET to measure the spatial distribution of tau pathology in Alzheimer's disease (AD) has been demonstrated in previous studies. The objective of this work was to evaluate tau deposition using 18F-PI-2620 PET in beta-amyloid positive subjects with a diagnosis of mild cognitive impairment (MCI) or mild AD dementia and characterize it with respect to amyloid deposition, cerebrospinal fluid (CSF) assessment, hippocampal volume, and cognition. METHODS: Subjects with a diagnosis of MCI due to AD or mild AD dementia and a visually amyloid-positive 18F-florbetaben PET scan (n=74, 76 ± 7 years, 38 females) underwent a baseline 18F-PI-2620 PET, T1-weighted magnetic resonance imaging (MRI), CSF assessment (Aß42/Aß40 ratio, p-tau, t-tau) (n=22) and several cognitive tests. A 1-year follow-up 18F-PI-2620 PET scans and cognitive assessments were done in 15 subjects. RESULTS: Percentage of visually tau-positive scans increased with amyloid-beta deposition measured in 18F-florbetaben Centiloids (CL) (7.7% (<36 CL), 80% (>83 CL)). 18F-PI-2620 standardized uptake value ratio (SUVR) was correlated with increased 18F-florbetaben CL in several regions of interest. Elevated 18F-PI-2620 SUVR (fusiform gyrus) was associated to high CSF p-tau and t-tau (p=0.0006 and p=0.01, respectively). Low hippocampal volume was associated with increased tau load at baseline (p=0.006 (mesial temporal); p=0.01 (fusiform gyrus)). Significant increases in tau SUVR were observed after 12 months, particularly in the mesial temporal cortex, fusiform gyrus, and inferior temporal cortex (p=0.04, p=0.047, p=0.02, respectively). However, no statistically significant increase in amyloid-beta load was measured over the observation time. The MMSE (Recall score), ADAS-Cog14 (Word recognition score), and CBB (One-card learning score) showed the strongest association with tau deposition at baseline. CONCLUSIONS: The findings support the hypothesis that 18F-PI-2620 PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD with significant correlations with hippocampal volume, CSF biomarkers, and amyloid-beta load. Furthermore, quantifiable increases in 18F-PI-2620 SUVR over a 12-month period in regions with early tau deposition are consistent with the hypothesis that cortical tau is associated with cognitive impairment. This study supports the utility of 18F-PI-2620 PET to assess tau deposits in an early AD population. Quantifiable tau load and its corresponding increase in early AD cases could be a relevant target engagement marker in clinical trials of anti-amyloid and anti-tau agents. TRIAL REGISTRATION: Data used in this manuscript belong to a tau PET imaging sub-study of the elenbecestat MissionAD Phase 3 program registered in ClinicalTrials.gov ( NCT02956486 ;  NCT03036280 ).

18F-PI-2620 Tau PET Improves the Imaging Diagnosis of Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy movement disorder that can be imaged by the 18F-labeled tau PET tracer 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine (18F-PI-2620). The in vivo diagnosis is currently established on clinical grounds and supported by midbrain atrophy estimation in structural MRI. Here, we investigate whether 18F-PI-2620 tau PET has the potential to improve the imaging diagnosis of PSP. Methods: In this multicenter observational study, dynamic (0-60 min after injection) 18F-PI-2620 PET and structural MRI data for 36 patients with PSP, 22 with PSP-Richardson syndrome, and 14 with a clinical phenotype other than Richardson syndrome (i.e., variant PSP) were analyzed along with data for 10 age-matched healthy controls (HCs). The PET data underwent kinetic modeling, which resulted in distribution volume ratio (DVR) images. These and the MR images were visually assessed by 3 masked experts for typical PSP signs. Furthermore, established midbrain atrophy parameters were measured in structural MR images, and regional DVRs were measured in typical tau-in-PSP target regions in the PET data. Results: Visual assessments discriminated PSP patients and HCs with an accuracy of 63% for MRI and 80% for the combination of MRI and 18F-PI-2620 PET. As compared with patients of the PSP-Richardson syndrome subgroup, those of the variant PSP subgroup profited more in terms of sensitivity from the addition of the visual 18F-PI-2620 PET to the visual MRI information (35% vs. 22%). In quantitative image evaluation, midbrain-to-pons area ratio and globus pallidus DVRs discriminated best between the PSP patients and HCs, with sensitivities and specificities of 83% and 90%, respectively, for MRI and 94% and 100%, respectively, for the combination of MRI and 18F-PI-2620 PET. The gain of sensitivity by adding 18F-PI-2620 PET to MRI data was more marked in clinically less affected patients than in more affected patients (37% vs. 19% for visual, and 16% vs. 12% for quantitative image evaluation). Conclusion: These results provide evidence for an improved imaging-based PSP diagnosis by adding 18F-PI-2620 tau PET to structural MRI. This approach seems to be particularly promising at earlier disease stages and could be of value both for improving early clinical PSP diagnosis and for enriching PSP cohorts for trials of disease-modifying drugs.

Radiotracer stereochemistry affects substrate affinity and kinetics for improved imaging of system xC- in tumors.

Amino acid utilization is perturbed in cancer cells, which rewire their metabolism to support cell survival and proliferation. This metabolic reprogramming can be exploited for diagnostic purposes through positron emission tomography imaging of fluorine-18 labeled amino acids. Despite its promise, little is known regarding transporter-recognition of non-natural amino acid stereoisomers or their utility for cancer imaging. We report here the synthesis and in vivo characterization of a radiolabeled amino acid (R)-4-(3-18F-fluoropropyl)-ʟ-glutamate ([18F]FRPG) and compared its tumor imaging properties to the 4S-isomer, [18F]FSPG. Methods: [18F]FRPG and [18F]FSPG uptake was assessed in H460 lung cancer cells, with efflux measured 30 min after removal of exogenous activity. Specificity of [18F]FRPG for system xC- was further examined following transporter inhibition and blocking studies with system xC- substrates. [18F]FRPG and [18F]FSPG pharmacokinetics was next quantified in mice bearing subcutaneous A549, H460, VCAP and PC3 tumors, with mice bearing A549 tumors imaged by PET/CT. To better-understand differential tumor retention, radiometabolite analysis was performed on tissue and blood samples after imaging. Next, [18F]FRPG and [18F]FSPG retention in lipopolysaccharide-treated lungs were compared to an orthotopic H460 lung cancer model. Finally, the sensitivity of [18F]FRPG to manipulation of the redox environment was examined in cell and in vivo models. Results: [18F]FRPG was specifically transported across the plasma membrane by the cystine/glutamate antiporter system xC- and retained at high levels in multiple tumor models. Conversely, [18F]FRPG was rapidly extracted from the blood and cleared from tissues with low system xC- expression. Due to its favorable imaging properties, tumor-to-blood ratios ≥10 were achieved with [18F]FRPG, which were either equal to or greater than [18F]FSPG. In addition, [18F]FRPG retention in orthotopic lung tumors with high system xC- expression was 2.5-fold higher than inflamed tissue, allowing for clear tumor visualization. In vivo, [18F]FRPG and [18F]FSPG were metabolized to a single species, with [18F]FRPG showing a higher percentage of parent radiotracer in tumors compared to [18F]FSPG. [18F]FRPG was sensitive to redox manipulations and tumor retention was reduced following treatment with liposomal doxorubicin in mice bearing ovarian tumors. Conclusions: Given the fast clearance and low background retention of [18F]FRPG throughout the body, this radiotracer holds promise for the imaging of system xC- activity and treatment response monitoring in tumors of the thorax, abdomen, and head and neck. [18F]FRPG PET imaging provides a sensitive noninvasive measure of system xC- and excellent properties for cancer imaging.

18F-FSPG PET/CT Imaging of System xC- Transporter Activity in Patients with Primary and Metastatic Brain Tumors.

Background The PET tracer (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (18F-FSPG) targets the system xC- cotransporter, which is overexpressed in various tumors. Purpose To assess the role of 18F-FSPG PET/CT in intracranial malignancies. Materials and Methods Twenty-six patients (mean age, 54 years ± 12; 17 men; 48 total lesions) with primary brain tumors (n = 17) or brain metastases (n = 9) were enrolled in this prospective, single-center study (ClinicalTrials.gov identifier: NCT02370563) between November 2014 and March 2016. A 30-minute dynamic brain 18F-FSPG PET/CT scan and a static whole-body (WB) 18F-FSPG PET/CT scan at 60-75 minutes were acquired. Moreover, all participants underwent MRI, and four participants underwent fluorine 18 (18F) fluorodeoxyglucose (FDG) PET imaging. PET parameters and their relative changes were obtained for all lesions. Kinetic modeling was used to estimate the 18F-FSPG tumor rate constants using the dynamic and dynamic plus WB PET data. Imaging parameters were correlated to lesion outcomes, as determined with follow-up MRI and/or pathologic examination. The Mann-Whitney U test or Student t test was used for group mean comparisons. Receiver operating characteristic curve analysis was used for performance comparison of different decision measures. Results 18F-FSPG PET/CT helped identify all 48 brain lesions. The mean tumor-to-background ratio (TBR) on the whole-brain PET images at the WB time point was 26.6 ± 24.9 (range: 2.6-150.3). When 18F-FDG PET was performed, 18F-FSPG permitted visualization of non-18F-FDG-avid lesions or allowed better lesion differentiation from surrounding tissues. In participants with primary brain tumors, the predictive accuracy of the relative changes in influx rate constant Ki and maximum standardized uptake value to discriminate between poor and good lesion outcomes were 89% and 81%, respectively. There were significant differences in the 18F-FSPG uptake curves of lesions with good versus poor outcomes in the primary brain tumor group (P < .05) but not in the brain metastases group. Conclusion PET/CT imaging with (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (18F-FSPG) helped detect primary brain tumors and brain metastases with a high tumor-to-background ratio. Relative changes in 18F-FSPG uptake with multi-time-point PET appear to be helpful in predicting lesion outcomes. Clinical trial registration no. NCT02370563 © RSNA, 2022 Online supplemental material is available for this article.

PET Imaging of System xC - in Immune Cells for Assessment of Disease Activity in Mice and Patients with Inflammatory Bowel Disease.

We aimed to explore whether the imaging of antiporter system xC - of immune cells with (4S)-4-(3-18F-fluoropropyl)-l-glutamate (18F-FSPG) PET can assess inflammatory bowel disease (IBD) activity in murine models and patients (NCT03546868). Methods: 18F-FSPG PET imaging was performed to assess IBD activity in mice with dextran sulfate sodium-induced and adoptive T-cell transfer-induced IBD and a cohort of 20 patients at a tertiary care center in South Korea. Immunohistochemical analysis of system xC - and cell surface markers was also studied. Results: Mice with experimental IBD showed increased intestinal 18F-FSPG uptake and xCT expression in cells positive (+) for CD11c, F4/80, and CD3 in the lamina propria, increases positively associated with clinical and pathologic disease activity. 18F-FSPG PET studies in patients, most of whom were clinically in remission or had mildly active IBD, showed that PET imaging was sufficiently accurate in diagnosing endoscopically active IBD and remission in patients and bowel segments. 18F-FSPG PET correctly identified all 9 patients with superficial or deep ulcers. Quantitative intestinal 18F-FSPG uptake was strongly associated with endoscopic indices of IBD activity. The number of CD68+xCT+ and CD3+xCT+ cells in 22 bowel segments from patients with ulcerative colitis and the number of CD68+xCT+ cells in 7 bowel segments from patients with Crohn disease showed a significant positive association with endoscopic indices of IBD activity. Conclusion: The assessment of system xC - in immune cells may provide diagnostic information on the immune responses responsible for chronic active inflammation in IBD. 18F-FSPG PET imaging of system xC - activity may noninvasively assess the IBD activity.

18F-GP1 Positron Emission Tomography and Bioprosthetic Aortic Valve Thrombus.

BACKGROUND: Bioprosthetic valve thrombosis may have implications for valve function and durability. OBJECTIVES: Using a novel glycoprotein IIb/IIIa receptor radiotracer 18F-GP1, we investigated whether positron emission tomography (PET)-computed tomography (CT) could detect thrombus formation on bioprosthetic aortic valves. METHODS: Ex vivo experiments were performed on human platelets and explanted bioprosthetic aortic valves. In a prospective cross-sectional study, patients with either bioprosthetic or normal native aortic valves underwent echocardiography, CT angiography, and 18F-GP1 PET-CT. RESULTS: Flow cytometric analysis, histology, immunohistochemistry, and autoradiography demonstrated selective binding of 18F-GP1 to activated platelet glycoprotein IIb/IIIa receptors and thrombus adherent to prosthetic valves. In total, 75 participants were recruited: 53 with bioprosthetic valves (median time from implantation 37 months [IQR: 12-80 months]) and 22 with normal native aortic valves. Three participants had obstructive valve thrombosis, and a further 3 participants had asymptomatic hypoattenuated leaflet thickening on CT angiography. All bioprosthetic valves, but none of the native aortic valves, demonstrated focal 18F-GP1 uptake on the valve leaflets: median maximum target-to-background ratio 2.81 (IQR: 2.29-3.48) vs 1.43 (IQR: 1.28-1.53) (P < 0.001). Higher 18F-GP1 uptake was independently associated with duration of valve implantation and hypoattenuated leaflet thickening. All 3 participants with obstructive valve thrombosis were anticoagulated for 3 months, leading to resolution of their symptoms, improvement in mean valve gradients, and a reduction in 18F-GP1 uptake. CONCLUSIONS: Adherence of activated platelets is a common and sustained finding on bioprosthetic aortic valves. 18F-GP1 uptake is higher in the presence of thrombus, regresses with anticoagulation, and has potential use as an adjunctive clinical tool. (18F-GP1 PET-CT to Detect Bioprosthetic Aortic Valve Thrombosis; NCT04073875).

GMP-Compliant Radiosynthesis of [18F]GP1, a Novel PET Tracer for the Detection of Thrombi.

Thrombus formation and thromboembolic events play important roles in various cardiovascular pathologies. The key receptor involved in platelet aggregation is the fibrinogen receptor glycoprotein IIb/IIIa. [18F]GP1, a derivative of the GPIIb/IIIa antagonist elarofiban, is a specific 18F-labeled small-molecule radiotracer that binds with high affinity to GPIIb/IIIa receptors of activated platelets. An improved, robust and fully automated radiosynthesis of [18F]GP1 has been developed. [18F]GP1 has been synthesized with decay corrected radiochemical yields of 38 ± 6%, with a radiochemical concentration up to 1900 MBq/mL, molar activities of 952-9428 GBq/µmol and a radio-chemical purity >98%. After determination of the optimal reaction conditions, in particular for HPLC separation, adaption of the reaction conditions to PET center requirements, validation of the manufacturing process and the quality control methods, the synthesis of [18F]GP1 was successfully implemented to GMP standards and was available for clinical application. We describe the GMP-compliant synthesis of the novel radiotracer [18F]GP1. Moreover, we provide some proof-of-concept examples for clinical application in the cardiovascular field. PET/CT with the novel small-molecular radiotracer [18F]GP1 may serve as a novel highly sensitive tool for visualizing active platelet aggregation at the molecular level.

Superiority of Formalin-Fixed Paraffin-Embedded Brain Tissue for in vitro Assessment of Progressive Supranuclear Palsy Tau Pathology With [ 18 F]PI-2620.

Objectives: Autoradiography on brain tissue is used to validate binding targets of newly discovered radiotracers. The purpose of this study was to correlate quantification of autoradiography signal using the novel next-generation tau positron emission tomography (PET) radiotracer [18F]PI-2620 with immunohistochemically determined tau-protein load in both formalin-fixed paraffin-embedded (FFPE) and frozen tissue samples of patients with Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP). Methods: We applied [18F]PI-2620 autoradiography to postmortem cortical brain samples of six patients with AD, five patients with PSP and five healthy controls, respectively. Binding intensity was compared between both tissue types and different disease entities. Autoradiography signal quantification (CWMR = cortex to white matter ratio) was correlated with the immunohistochemically assessed tau load (AT8-staining, %-area) for FFPE and frozen tissue samples in the different disease entities. Results: In AD tissue, relative cortical tracer binding was higher in frozen samples when compared to FFPE samples (CWMRfrozen vs. CWMRFFPE: 2.5-fold, p < 0.001), whereas the opposite was observed in PSP tissue (CWMRfrozen vs. CWMRFFPE: 0.8-fold, p = 0.004). In FFPE samples, [18F]PI-2620 autoradiography tracer binding and immunohistochemical tau load correlated significantly for both PSP (R = 0.641, p < 0.001) and AD tissue (R = 0.435, p = 0.016), indicating a high agreement of relative tracer binding with underlying pathology. In frozen tissue, the correlation between autoradiography and immunohistochemistry was only present in AD (R = 0.417, p = 0.014) but not in PSP tissue (R = -0.115, p = n.s.). Conclusion: Our head-to-head comparison indicates that FFPE samples show superiority over frozen samples for autoradiography assessment of PSP tau pathology by [18F]PI-2620. The [18F]PI-2620 autoradiography signal in FFPE samples reflects AT8 positive tau in samples of both PSP and AD patients.

Early detection of amyloid load using 18F-florbetaben PET.

BACKGROUND: A low amount and extent of Aß deposition at early stages of Alzheimer's disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aß accumulation using 18F-florbetaben PET. Quantitative thresholds for the early (SUVRearly) and established (SUVRestab) Aß deposition were developed, and the topography of early Aß deposition was assessed. Subsequently, Aß accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aß deposition. METHODS: The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aß-deposition continuum were defined based on the developed SUVR cutoffs: Aß-negative subjects, subjects with early Aß deposition ("gray zone"), and subjects with established Aß pathology. RESULTS: SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the "gray zone" or with established Aß pathology accumulated more amyloid over time than Aß-negative subjects. After a 4-year clinical follow-up, none of the Aß-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aß pathology progressed. Tau deposition was infrequent in those subjects without established Aß pathology. CONCLUSIONS: This study supports the utility of using two cutoffs for amyloid PET abnormality defining a "gray zone": a lower cutoff of 13.5 CL indicating emerging Aß pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention. TRIAL REGISTRATION: Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov ( NCT00928304 , NCT00750282 , NCT01138111 , NCT02854033 ) and EudraCT (2014-000798-38).

Initial evaluation of (4S)-4-(3-[18F]fluoropropyl)-L-glutamate (FSPG) PET/CT imaging in patients with head and neck cancer, colorectal cancer, or non-Hodgkin lymphoma.

PURPOSE: (4S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid ([18F]FSPG) measures system xC- transporter activity and shows promise for oncologic imaging. We present data on tumor uptake of this radiopharmaceutical in human subjects with head and neck cancer (HNC), colorectal cancer (CRC), and non-Hodgkin lymphoma (NHL). METHODS: A total of 15 subjects with HNC (n = 5), CRC (n = 5), or NHL (n = 5) were recruited (mean age 66.2 years, range 44-87 years). 301.4 ± 28.1 MBq (8.1 ± 0.8 mCi) of [18F]FSPG was given intravenously to each subject, and 3 PET/CT scans were obtained 0-2 h post-injection. All subjects also had a positive [18F]FDG PET/CT scan within 1 month prior to the [18F]FSPG PET scan. Semi-quantitative and visual comparisons of the [18F]FSPG and [18F]FDG scans were performed. RESULTS: [18F]FSPG showed strong uptake in all but one HNC subject. The lack of surrounding brain uptake facilitated tumor delineation in the HNC patients. [18F]FSPG also showed tumor uptake in all CRC subjects, but variable uptake in the NHL subjects. While the absolute [18F]FDG SUV values were comparable or higher than [18F]FSPG, the tumor-to-background SUV ratios were greater with [18F]FSPG than [18F]FDG. CONCLUSIONS: [18F]FSPG PET/CT showed promising results across 15 subjects with 3 different cancer types. Concordant visualization was mostly observed between [18F]FSPG and [18F]FDG PET/CT images, with some inter- and intra-individual uptake variability potentially reflecting differences in tumor biology. The tumor-to-background ratios were greater with [18F]FSPG than [18F]FDG in the cancer types evaluated. Future studies based on larger numbers of subjects and those with a wider array of primary and recurrent or metastatic tumors are planned to further evaluate the utility of this novel tracer.

Clinical Evaluation of (4S)-4-(3-[18F]Fluoropropyl)-L-glutamate (18F-FSPG) for PET/CT Imaging in Patients with Newly Diagnosed and Recurrent Prostate Cancer.

PURPOSE: (4S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid (18F-FSPG) is a radiopharmaceutical for PET imaging of system xC - activity, which can be upregulated in prostate cancer. We present data on the first evaluation of patients with newly diagnosed or recurrent prostate cancer with this radiopharmaceutical. EXPERIMENTAL DESIGN: Ten patients with primary and 10 patients with recurrent prostate cancer were enrolled in this prospective multicenter study. After injection of 300 MBq of 18F-FSPG, three whole-body PET/CT scans were obtained. Visual analysis was compared with step-section histopathology when available as well as other imaging studies and clinical outcomes. Metabolic parameters were measured semiquantitatively. Expression levels of xCT and CD44 were evaluated by IHC for patients with available tissue samples. RESULTS: 18F-FSPG PET showed high tumor-to-background ratios with a relatively high tumor detection rate on a per-patient (89%) and per-lobe (87%) basis. The sensitivity was slightly higher with imaging at 105 minutes in comparison with 60 minutes. The maximum standardized uptake values (SUVmax) for cancer was significantly higher than both normal (P < 0.005) and benign pathology (P = 0.011), while there was no significant difference between normal and benign pathology (P = 0.120). In the setting of recurrence, agreement with standard imaging was demonstrated in 7 of 9 patients (78%) and 13 of 18 lesions (72%), and revealed true local recurrence in a discordant case. 18F-FSPG accumulation showed moderate correlation with CD44 expression. CONCLUSIONS: 18F-FSPG is a promising tumor imaging agent for PET that seems to have favorable biodistribution and high cancer detection rate in patients with prostate cancer. Further studies are warranted to determine the diagnostic value for both initial staging and recurrence, and how it compares with other investigational radiotracers and conventional imaging modalities.

Tau PET imaging with 18F-PI-2620 in Patients with Alzheimer Disease and Healthy Controls: A First-in-Humans Study.

18F-PI-2620 is a PET tracer with high binding affinity for aggregated tau, a key pathologic feature of Alzheimer disease (AD) and other neurodegenerative disorders. Preclinically, 18F-PI-2620 binds to both 3-repeat and 4-repeat tau isoforms. The purpose of this first-in-humans 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 the safety and tolerability of this new tau PET tracer. Methods: Participants with a clinical diagnosis of probable AD and healthy controls (HCs) 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 noninvasive tracer kinetics and SUV ratio (SUVR) measured at different time points after injection, with the cerebellar cortex as the reference region. Time-activity curves and SUVR were assessed in AD and HC subjects, 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 after injection and fast washout from nontarget 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 subjects than in HCs. Very low background signal was observed in HCs. 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 after injection. A strong correlation (R2 > 0.93) was found between noninvasive DVR and SUVR for all imaging windows starting at more than 30 min after injection. Similar effect sizes between AD and HC groups were obtained across the different imaging windows. 18F-PI-2620 uptake in neocortical regions significantly correlated with the degree of cognitive impairment. Conclusion: Initial clinical data obtained in AD and HC subjects demonstrated a high image quality and excellent signal-to-noise ratio of 18F-PI-2620 PET for imaging tau deposition in AD subjects. Noninvasive quantification using DVR and SUVR for 30-min imaging windows between 30 and 90 min after injection-for example, 45-75 min-provides robust and significant discrimination between AD and HC subjects. 18F-PI-2620 uptake in expected regions correlates strongly with neurocognitive performance.