Progressive supranuclear palsy (PSP) is a primary 4R tauopathy. Postmortem studies identified six tau pathological stages with tau aggregation with involvement of the subthalamic nucleus and the globus pallidus, with further affliction of the striatum, cerebellum with dentate nucleus, frontal and/or occipital cortices. We aimed to test whether this staging system is also observed when an unsupervised machine learning model is used to analyze in vivo [18F]PI-2620 tau PET imaging data. Furthermore, regional differences in tau tracer binding in different PSP subtypes and corresponding clinical profiles were investigated. Methods We analyzed imaging and clinical data of 120 patients with the clinical diagnosis of PSP and of 16 healthy controls. Dynamic [18F]PI-2620 PET imaging in a multicenter setting (sites in Germany and Australia) was performed over 60min. After kinetic modeling, parametric distribution volume ratio images were analyzed and classified into different pattern subtypes and stages by use of the SuStaIn algorithm. Regional differences in tau tracer binding were assessed using statistical parametric mapping. Results The SuStaIn model distinguished three patterns of [18F]PI-2620 binding: i) a subcortical pattern, ii) a rhombencephalic pattern, and iii) a cortical pattern. The subcortical pattern showed a spatiotemporal distribution similar to the previously published PSP postmortem staging system. Subjects in different SuStaIn-derived patterns showed different clinical characteristics, including a significant association with sex (P < 0.001). Conclusion These results provide motivation to further develop [18F]PI-2620 as an imaging biomarker of PSP. They also demonstrate the potential of the SuStaIn model to reveal so-far-unknown tau tracer binding patterns in PSP, with possible implications for improved phenotyping and future anti-tau treatment decisions.

[18F]fluorodeprenyl-D2 ([18F]F-DED) positron emission tomography (PET) imaging detects reactive astrogliosis in patients with autoimmune encephalitis (AIE) and multiple system atrophy (MSA). Although dynamic 60-min acquisitions are established, shorter static imaging protocols are desirable for severely impaired patients. This study investigated the feasibility of short static time windows for [18F]F-DED PET imaging in AIE and MSA. Dynamic 60-min [18F]F-DED PET scans were analyzed in 20 patients with AIE, 20 patients with MSA (MSA-P/MSA-C), and 16 controls (CTRL). Disease-related lesions were manually segmented based on visually detectable positive PET-signal in AIE and MSA predilection sites (i.e. mesial temporal lobe, posterior putamen, cerebellar deep white matter), and standardized uptake value ratios (SUVr; cerebellar cortex as a reference tissue) were calculated for consecutive 10-min intervals. Advanced kinetic parameters (DVR, VTr) were derived using Logan plot and a one-tissue compartment model (1TC2k) with image-derived input functions, both applying the cerebellar cortex as a reference tissue. Static images acquired between 10 and 60 min p.i. showed good image contrast and signal-to-noise ratio. SUVr of lesions increased over time and approached a plateau at approximately 50–60 min p.i.. The strongest agreement between SUVr and DVR was observed between 30 and 50 min p.i.. Late-phase SUVr outperformed kinetic parameters in discriminating lesions from healthy tissue in both AIE and MSA. Short static [18F⁸ ]F-DED PET acquisitions are clinically robust for detecting neuroinflammation in AIE and MSA. A late static acquisition between 30–50 min p.i. provides the optimal balance between accuracy and scanning efficiency.

Neurodegenerative 4-repeat (4R) tauopathies commonly manifest as progressive supranuclear palsy (PSP). PSP patients show elevated PI-2620-PET in subcortical 4R tau predilection sites (e.g., globus pallidus), suggesting PI-2620-PET as a promising 4R tau neuroimaging candidate. However, optimal quantification of PI-2620-PET in 4R tauopathies remains challenging, as conventional cerebellar tau-PET reference regions also accumulate 4R tau. We aimed to use unbiased image-derived input function (IDIF) PET data to determine an optimized PET reference region for in vivo quantification of 4R tau. We obtained 60-minute dynamic PI-2620-PET in 54 PSP Richardson Syndrome (PSP-RS) patients and 19 healthy controls (HC), applying IDIF-modeling using carotid timeseries to assess unbiased PI-2620-PET binding and determine total distribution volume (VT). Through an iterative approach, we intensity-normalized VT-images against white-matter regions in the Hammers brain atlas, identifying regions where intensity-normalized pallidum PET values showed the largest PSP-RS vs. HC differences. White-matter regions with strongest PSP-RS vs. HC differences surviving multiple-comparison correction were summarized into a single reference region spanning bilateral temporo-orbital white-matter. This ROI was then used to determine SUVRs using conventional 20-40 minute PI-2620-PET data in PSP-RS, a PSP-non-RS validation sample ( n  = 63), as well as non-tau disease controls (i.e., alpha-synucleinopathies, n  = 20; Alzheimer's disease, n  = 23). Using PI-2620 SUVRs obtained with the temporo-orbital white-matter reference, we detected strong PSP-RS vs. HC group differences in basal ganglia SUVRs using voxel-wise comparisons ( p  <0.001, FWE-cluster corrected). Similar basal ganglia differences were detected for PSP-non-RS vs. HC, but not for alpha-syn (no group differences) or AD vs. HC (cortical AD-like group differences). In contrast, minimal group differences were found using a conventional inferior cerebellar grey matter reference region. Our findings strongly suggest temporo-orbital white-matter is superior to inferior cerebellum as a reference region for PI-2620-PET imaging in 4R tauopathies, due to increased sensitivity and purported specificity for 4R tau.

Background Amyloid PET imaging enables the in vivo visualization and quantification of amyloid-beta deposits in the brain. In research and clinical settings, it is further used to monitor amyloid-beta burden as well as the biological response to disease-modifying therapies. Amyloid-beta targeting monoclonal antibodies (mAbs) such as lecanemab and donanemab were designed to reduce brain amyloid-beta burden. If the PET tracer and the mAbs would bind to the same site, the PET signal may be impacted in patients undergoing therapy. Binding interaction studies were conducted to verify the reliability of PET readouts in this setting. The aim of this study was to investigate whether lecanemab or donanemab interfere with the binding of the amyloid PET tracer florbetaben to aggregated amyloid-beta deposits in vitro. Methods Human Alzheimer's disease (AD) brain tissue from various sources was used to assess potential interactions between florbetaben and lecanemab or donanemab. Three complementary approaches were used to confirm target binding and to study potential interactions: (1) competitive immunohistochemistry (IHC), (2) competitive autoradiography (ARG), and (3) ligand binding assays (LBA). Results Across all three sets of experiments, no evidence of competition or inhibition of florbetaben binding to amyloid-beta deposits by lecanemab or donanemab was observed. Autoradiography demonstrated robust tracer binding to amyloid-beta plaques that was unaffected by incubation with excess antibody. Similarly, IHC and LBA experiments confirmed that florbetaben and the tested mAbs target distinct binding sites on amyloid-beta aggregates. Conclusions These results demonstrate that neither lecanemab nor donanemab interfere with florbetaben binding to amyloid-beta plaques in vitro, further validating its use in this setting. While the current data are limited to in-vitro experiments, they further support the use of florbetaben PET for monitoring amyloid-beta changes during treatment with amyloid-beta targeting therapies.

[18F]PI-2620 is a promising radiopharmaceutical for positron emission tomography (PET) imaging of both Alzheimer's disease (AD) and non-Alzheimer's disease (non-AD) tauopathies in humans. An array of fluorinated derivatives of the carbazole scaffold of PI-2620 were synthesized and evaluated. In vitro binding assays with [3H]PI-2620 in human tissues with AD, progressive supranuclear palsy, and corticobasal degeneration, combined with in silico predictions of blood-brain barrier permeability, led to the selection and radiosynthesis of [18F]F-4 as a promising radiotracer. In vivo PET imaging with [18F]F-4 in healthy rats showed brain uptake and kinetics suitable for neuroimaging, similar to those of [18F]PI-2620. A first-in-human PET imaging study in a healthy subject as well as a patient with AD, in comparison with [18F]PI-2620 in the same AD subject, confirmed that [18F]F-4 is an alternative radiopharmaceutical for imaging tau protein.

Ziel/Aim: Positron-emission-tomography (PET) imaging with the novel monoamine oxidase B (MAO-B) radiotracer [18F]fluorodeprenyl-D2 ([18F]F-DED) to detect reactive astrocytosis enables imaging of neuroinflammation in patients with autoimmune-encephalitis (AIE) and multiple system atrophy (MSA). This study investigated the use of static time windows for [18F]F-DED MAO-B-PET imaging of AIE and MSA.

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 (β = 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 (β = -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.

Florbetaben (FBB) is a radiopharmaceutical approved by the FDA and EMA in 2014 for the positron emission tomography (PET) imaging of brain amyloid deposition in patients with cognitive impairment who are being evaluated for Alzheimer’s disease (AD) or other causes of cognitive decline. Initially, the clinical adoption of FBB PET faced significant barriers, including reimbursement challenges and uncertainties regarding its integration into diagnostic clinical practice. This review examines the progress made in overcoming these obstacles and describes the concurrent evolution of the diagnostic landscape. Advances in quantification methods have further strengthened the traditional visual assessment approach. Over the past decade, compelling evidence has emerged, demonstrating that amyloid PET has a strong impact on AD diagnosis, management, and outcomes across diverse clinical scenarios, even in the absence of amyloid-targeted therapies. Amyloid PET imaging has become essential in clinical trials and the application of new AD therapeutics, particularly for confirming eligibility criteria (i.e., the presence of amyloid plaques) and monitoring biological responses to amyloid-lowering therapies. Since its approval, FBB PET has transitioned from a purely diagnostic tool aimed primarily at excluding amyloid pathology to a critical component in AD drug development, and today, it is essential in the diagnostic workup and therapy management of approved AD treatments.

Background: The gastrin-releasing peptide receptor (GRPr) is highly overexpressed in several solid tumors, including treatment-naïve and recurrent prostate cancer. [68Ga]Ga-RM2 is a well-established radiotracer for PET imaging of GRPr, and [177Lu]Lu-RM2 has been proposed as a therapeutic alternative for patients with heterogeneous and/or low expression of PSMA. In this study, we aimed to evaluate the expression of GRPr and PSMA in a group of patients diagnosed with castration-resistant prostate cancer (mCRPC) by means of PET imaging. Methods: Seventeen mCRPC patients referred for radio-ligand therapy (RLT) were enrolled and underwent [68Ga]Ga-PSMA-11 and [68Ga]Ga-RM2 PET/CT imaging, 8.8 ± 8.6 days apart, to compare the biodistribution of each tracer. Uptake in healthy organs and tumor lesions was assessed by SUV values, and tumor-to-background ratios were analyzed. Results: [68Ga]Ga-PSMA-11 showed significantly higher uptake in tumor lesions in bone, lymph nodes, prostate, and soft tissues and detected 23% more lesions compared to [68Ga]Ga-RM2. In 4/17 patients (23.5%), the biodistribution of both tracers was comparable. Conclusions: Our results show that in our cohort of mCRPC patients, PSMA expression was higher compared to GRPr. Nevertheless, RLT with [177Lu]Lu-RM2 may be an alternative treatment option for selected patients or patients in earlier disease stages, such as biochemical recurrence.

<p>PDF file- 354K, Detailed information on chemistry, radiochemistry and additional biological characterization</p>

PDF file- 354K, Detailed information on chemistry, radiochemistry and additional biological characterization

<p>MPG Movie file - 4626K, Y94-9392 H460 Tumor PET</p>

AbstractPurpose:18F-labeled small molecules targeting adaptations of tumor metabolism possess the potential for early tumor detection with high sensitivity and specificity by positron emission tomography (PET) imaging. Compounds tracing deranged pathways other than glycolysis may have advantages in situations where 2-[18F]fluoro-2-deoxy-d-glucose (FDG) has limitations. The aim of this study was the generation of a metabolically stable 18F-labeled glutamate analogue for PET imaging of tumors.Experimental Design: Derivatives of l-glutamate were investigated in cell competition assays to characterize the responsible transporter. An automated radiosynthesis was established for the most promising candidate. The resulting 18F-labeled PET tracer was characterized in a panel of in vitro and in vivo tumor models. Tumor specificity was investigated in the turpentine oil-induced inflammation model in rats.Results: A fluoropropyl substituted glutamate derivative showed strong inhibition in cell uptake assays. The radiosynthesis was established for (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (BAY 94-9392). Tracer uptake studies and analysis of knockdown cells showed specific transport of BAY 94-9392 via the cystine/glutamate exchanger designated as system xC−. No metabolites were observed in mouse blood and tumor cells. PET imaging with excellent tumor visualization and high tumor to background ratios was achieved in preclinical tumor models. In addition, BAY 94-9392 did not accumulate in inflammatory lesions in contrast to FDG.Conclusions: BAY 94-9392 is a new tumor-specific PET tracer which could be useful to examine system xC− activity in vivo as a possible hallmark of tumor oxidative stress. Both preclinical and clinical studies are in progress for further characterization. Clin Cancer Res; 17(18); 6000–11. ©2011 AACR.

Purpose: Overexperssion of Gastrin-releasing-peptide receptor (GRPr) in prostate carcinoma (PCa) suggests new means in the detection of prostate cancer foci. The bombesin derivative RM2 (DOTA-4-amino-1-carboxy­methyl­piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) is a GRPr antagonist with strong binding affinity. Based on promising results from a first-in-man study on PCa detection in patients with local disease, a Phase I/II study was initiated and the ability of [68Ga]Ga-RM2 PET/CT to detect PCa lesions was compared with [18F]fluoromethylcholine ([18F]FCH) PET/CT and multiparameteric prostate Magnetic Resonance Imaging (mpMRI).Methods: This Phase I/II study was conductedwith a pre-specified interim analysis following the enrollment of 30 biopsy-positive PCa subjects, stratified into low, intermediate and high pretreatment risk of extra-glandular metastases with reference to NCCN criteria. Each subject had PCa detected by transrectal ultrasound guided prostate biopsy and subjects were scheduled to undergo prostatectomy with pelvic lymph node (LN) dissection in intermediate and high risk patients. Following administration of an intravenous dose of 140 MBq of [68Ga]Ga-RM2,imaging was conducted at 60 min. p.i.. Twenty-five (25/30) subjects had concomitant [18F]FCH PET/CT imaging. All patients underwent mpMRI. Intra-prostatic and pelvic nodal PET/CT findings were correlated with histopathologic results.Results: High uptake of [68Ga]Ga-RM2 was seen in pancreas and the urinary system with very low background uptake in the rest of the abdomen or thorax. Despite of high bladder activity, focal intraprostatic uptake was readily well detectable. Of overall 312 analyzed regions, 120 regions (4 to 8 lesions per-patient) showed abnormal finding in the prostate gland. In a region-based analysis overall sensitivity and specificity of [68Ga]Ga-RM2 PET/CT in the detection of primary tumor were 74% and 90%, respectively; while it was 60% and 80% for [18F]FCH PET/CT and 72% and 89% for mpMRI. Although, the overall sensitivity of [68Ga]Ga-RM2 PET/CT was higher comparing to [18F]FCH PET/CT and mpMRI; however, the statistical analysis showed only significant difference between [68Ga]Ga-RM2 PET/CT and [18F]FCH PET/CT in intermediate-risk group (P=0.01) and [68Ga]Ga-RM2 PET/CT and mpMRT in high-risk group (p=0.03). [68Ga]Ga-RM2 PET/CT correctly detected 2 histopathologically verified LN metastases in 2 high risk patients; while 18F-FCH PET/CT only identified the LN lesion in 1 patient.Conclusion: [68Ga]Ga-RM2 is a promising new PET-tracer with a high detection rate for intraprostatic PCa. While index lesion detection rates were similar in both PET/CT studies, the improved specificity of [68Ga]Ga-RM2 for canver versus BPH renders it notably better than [18F]FCH in the detection of intraprostatic lesions. In addition, GRP-R-based imaging seems to play a complementary role to Choline-based imaging for full characterization of PCa extent, biopsy guidance in low and intermediate metastatic risk PCa patients and has the potential to discriminate them from whom of those at higher risks.Trial Registeration number: EudraCT-Nr.: 2014-003027-21, Date: 10 June, 2014

Abstract 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 β-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 β-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.

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. 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 (Aβ42/Aβ40 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. 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. 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. 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 ).

Neuroinflammation is a process occurring in neurodegenerative diseases, such as Alzheimer’s Disease (AD) and parkinsonian syndromes. In light of emerging disease modifying trials, objective biomarkers are urgently needed. Here, we target reactive astrogliosis for biomarker development in a pilot cohort of Multiple System Atrophy (MSA), in which key pathology and associated neuroinflammation are regionally more restricted than in AD, but more pronounced than in Parkinson’s Disease (PD). We combine glial fibrillary acidic protein (GFAP) as fluid-based biomarker with [ 18 F]D2-Deprenyl-(DED)-PET imaging, a novel PET tracer targeting MAO-B, for comprehensive characterization of reactive astrogliosis in this model disease. GFAP levels were analyzed in plasma samples of 23 MSA and 22 PD patients, as well as in CSF samples of 14 MSA and 14 PD patients. In a subset of patients (4 MSA-P, 7 MSA-C and 3 PD), first-in-human [ 18 F]DED-PET imaging was performed. Fluid-based and PET-imaging biomarker levels were cross-sectionally compared, followed by correlation to clinical disease severity as indicated by UMSARS (Unified Multiple System Atrophy Rating Scale) and MDS-UPDRS (MDS Unified Parkinson’s Disease Rating Scale). Correlation between fluid-based biomarkers and PET imaging signals was performed. Two additional patients were on rasagiline treatment and proved target engagement of [ 18 F]DED-PET imaging. [ 18 F]DED-PET imaging showed significantly higher SUVr signals in various regions of MSA when compared to PD. Signal increases were seen in phenotype-specific target regions with higher putaminal tracer binding in MSA-P and higher cerebellar tracer binding in MSA-C patients (Fig. 1). Decreased [ 18 F]DED-PET tracer signal was detected in patients on rasagiline treatment, indicating sufficient blocking (Fig. 2). While CSF and plasma GFAP levels did not differ between MSA and PD, GFAP levels in both biofluids correlated with disease severity in MSA (p < 0.05), but not in PD. We present first-in-human data on a novel PET tracer to detect reactive astrogliosis in MSA. While [ 18 F]DED-PET imaging identifies disease- and entity-specific regional astrogliosis, fluid biomarkers representing the overall level of astrogliosis appear to reflect clinical disease burden. Translation of these biomarkers into other neurodegenerative diseases, such as AD, should be pursued.

Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting-state fMRI connectomics with both 2 nd generation 18 F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4-repeat tauopathies and post-mortem cell-type-specific regional tau assessments from two independent progressive supranuclear palsy patient samples ( n = 97 and n = 96). We find that inter-regional connectivity is associated with higher inter-regional correlation of both tau-PET and post-mortem tau levels in 4-repeat tauopathies. In regional cell-type specific post-mortem tau assessments, this association is stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with neuronal tau accumulation. Using tau-PET we find further that patient-level tau patterns are associated with the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies.

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-(3-18 F-fluoropropyl)-ʟ-glutamate ([ 18 F]FRPG) and compared its tumor imaging properties to the 4S-isomer, [ 18 F]FSPG.Methods: [ 18 F]FRPG and [ 18 F]FSPG uptake was assessed in H460 lung cancer cells, with efflux measured 30 min after removal of exogenous activity.Specificity of [ 18 F]FRPG for system xC -was further examined following transporter inhibition and blocking studies with system xC -substrates.[ 18 F]FRPG and [ 18 F]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, [ 18 F]FRPG and [ 18 F]FSPG retention in lipopolysaccharide-treated lungs were compared to an orthotopic H460 lung cancer model.Finally, the sensitivity of [ 18 F]FRPG to manipulation of the redox environment was examined in cell and in vivo models.Results: [ 18 F]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, [ 18 F]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 [ 18 F]FRPG, which were either equal to or greater than [ 18 F]FSPG.In addition, [ 18 F]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, [ 18 F]FRPG and [ 18 F]FSPG were metabolized to a single species, with [ 18 F]FRPG showing a higher percentage of parent radiotracer in tumors compared to [ 18 F]FSPG.[ 18 F]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 [ 18 F]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.[ 18 F]FRPG PET imaging provides a sensitive noninvasive measure of system xC -and excellent properties for cancer imaging.