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AimNeuroinflammation plays a key role in both the pathogenesis and the progression of cerebral cavernous malformations (CCM). Flutriciclamide ([18F]GE-180) is a translocator protein (TSPO) targeting positron emission tomography (PET) tracer, developed for imaging neuroinflammation. The objectives of this study were to describe characteristics of flutriciclamide uptake in different brain tissue regions in CCM patients compared to controls, and to evaluate flutriciclamide uptake and iron deposition within CCM lesions.Materials and methodsFive patients with CCM and six controls underwent a 60 or 90 min continuous PET/MRI scan following 315 ± 68.9 MBq flutriciclamide administration. Standardized uptake value (SUV) and standardized uptake value ratio (SUVr) were obtained using the striatum as a pseudo-reference. Quantitative susceptibility maps (QSM) were used to define the location of the vascular malformation and calculate the amount of iron deposition in each lesion.ResultsIncreased flutriciclamide uptake was observed in all CCM lesions. The temporal pole demonstrated the highest radiotracer uptake; the paracentral lobule, cuneus and hippocampus exhibited moderate uptake; while the striatum had the lowest uptake, with average SUVs of 0.66, 0.55, 0.63, 0.55, and 0.33 for patient with CCM and 0.57, 0.50, 0.48, 0.42, and 0.32 for controls, respectively. Regional SUVr showed similar trends. The average SUV and QSM values in CCM lesions were 0.58 ± 0.23 g/ml and 0.30 ± 0.10 ppm. SUVs and QSM were positively correlated in CCM lesions (r = 0.53, p = 0.03).ConclusionThe distribution of flutriciclamide ([18F]GE-180) in the human brain and CCM lesions demonstrated the potential of this TSPO PET tracer as a marker of neuroinflammation that may be relevant for characterizing CCM disease progression along with QSM.

AimNeuroinflammation plays a key role in both the pathogenesis and the progression of cerebral cavernous malformations (CCM). Flutriciclamide ([18F]GE-180) is a translocator protein (TSPO) targeting positron emission tomography (PET) tracer, developed for imaging neuroinflammation. The objectives of this study were to describe characteristics of flutriciclamide uptake in different brain tissue regions in CCM patients compared to controls, and to evaluate flutriciclamide uptake and iron deposition within CCM lesions.Materials and methodsFive patients with CCM and six controls underwent a 60 or 90 min continuous PET/MRI scan following 315 ± 68.9 MBq flutriciclamide administration. Standardized uptake value (SUV) and standardized uptake value ratio (SUVr) were obtained using the striatum as a pseudo-reference. Quantitative susceptibility maps (QSM) were used to define the location of the vascular malformation and calculate the amount of iron deposition in each lesion.ResultsIncreased flutriciclamide uptake was observed in all CCM lesions. The temporal pole demonstrated the highest radiotracer uptake; the paracentral lobule, cuneus and hippocampus exhibited moderate uptake; while the striatum had the lowest uptake, with average SUVs of 0.66, 0.55, 0.63, 0.55, and 0.33 for patient with CCM and 0.57, 0.50, 0.48, 0.42, and 0.32 for controls, respectively. Regional SUVr showed similar trends. The average SUV and QSM values in CCM lesions were 0.58 ± 0.23 g/ml and 0.30 ± 0.10 ppm. SUVs and QSM were positively correlated in CCM lesions (r = 0.53, p = 0.03).ConclusionThe distribution of flutriciclamide ([18F]GE-180) in the human brain and CCM lesions demonstrated the potential of this TSPO PET tracer as a marker of neuroinflammation that may be relevant for characterizing CCM disease progression along with QSM.

Purpose: Tracer kinetic modeling of tissue time activity curves and the individual input function based on arterial blood sampling and metabolite correction is the gold standard for quantitative characterization of microglia activation by PET with the translocator protein (TSPO) ligand 18F-GE-180. This study tested simplified methods for quantification of 18F-GE-180 PET. Methods: Dynamic 18F-GE-180 PET with arterial blood sampling and metabolite correction was performed in five healthy volunteers and 20 liver-transplanted patients. Population-based input function templates were generated by averaging individual input functions normalized to the total area under the input function using a leave-one-out approach. Individual population-based input functions were obtained by scaling the input function template with the individual parent activity concentration of 18F-GE-180 in arterial plasma in a blood sample drawn at 27.5 min or by the individual administered tracer activity, respectively. The total 18F-GE-180 distribution volume (VT) was estimated in 12 regions-of-interest (ROIs) by the invasive Logan plot using the measured or the population-based input functions. Late ROI-to-whole-blood and ROI-to-cerebellum ratio were also computed. Results: Correlation with the reference VT (with individually measured input function) was very high for VT with the population-based input function scaled with the blood sample and for the ROI-to-whole-blood ratio (Pearson correlation coefficient = 0.989 ± 0.006 and 0.970 ± 0.005). The correlation was only moderate for VT with the population-based input function scaled with tracer activity dose and for the ROI-to-cerebellum ratio (0.653 ± 0.074 and 0.384 ± 0.177). Reference VT, population-based VT with scaling by the blood sample, and ROI-to-whole-blood ratio were sensitive to the TSPO gene polymorphism. Population-based VT with scaling to the administered tracer activity and the ROI-to-cerebellum ratio failed to detect a polymorphism effect. Conclusion: These results support the use of a population-based input function scaled with a single blood sample or the ROI-to-whole-blood ratio at a late time point for simplified quantitative analysis of 18F-GE-180 PET. [ABSTRACT FROM AUTHOR]

Aim: Neuroinflammation plays a key role in both the pathogenesis and the progression of cerebral cavernous malformations (CCM). Flutriciclamide ([ 18 F]GE-180) is a translocator protein (TSPO) targeting positron emission tomography (PET) tracer, developed for imaging neuroinflammation. The objectives of this study were to describe characteristics of flutriciclamide uptake in different brain tissue regions in CCM patients compared to controls, and to evaluate flutriciclamide uptake and iron deposition within CCM lesions., Materials and Methods: Five patients with CCM and six controls underwent a 60 or 90 min continuous PET/MRI scan following 315 ± 68.9 MBq flutriciclamide administration. Standardized uptake value (SUV) and standardized uptake value ratio (SUVr) were obtained using the striatum as a pseudo-reference. Quantitative susceptibility maps (QSM) were used to define the location of the vascular malformation and calculate the amount of iron deposition in each lesion., Results: Increased flutriciclamide uptake was observed in all CCM lesions. The temporal pole demonstrated the highest radiotracer uptake; the paracentral lobule, cuneus and hippocampus exhibited moderate uptake; while the striatum had the lowest uptake, with average SUVs of 0.66, 0.55, 0.63, 0.55, and 0.33 for patient with CCM and 0.57, 0.50, 0.48, 0.42, and 0.32 for controls, respectively. Regional SUVr showed similar trends. The average SUV and QSM values in CCM lesions were 0.58 ± 0.23 g/ml and 0.30 ± 0.10 ppm. SUVs and QSM were positively correlated in CCM lesions ( r = 0.53, p = 0.03)., Conclusion: The distribution of flutriciclamide ([ 18 F]GE-180) in the human brain and CCM lesions demonstrated the potential of this TSPO PET tracer as a marker of neuroinflammation that may be relevant for characterizing CCM disease progression along with QSM., Competing Interests: JL has research funding from GE HealthCare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kim, Lupo, Chen, Pampaloni, VanBrocklin, Narvid, Kim and Seo.)

Purpose: Neuroinflammation plays a critical role in various neuropathological conditions, and hence there is renewed interest in the translocator protein (TSPO) as a biomarker of microglial activation and macrophage infiltration in the brain. This is reflected in the large amount of research conducted seeking to replace the prototypical PET radiotracer C-R-PK11195 with a TSPO ligand with higher performance. Here we report the in vivo preclinical investigation of the novel TSPO tracer F-GE-180 in a rat model of stroke. Methods: Focal cerebral ischaemia was induced in Wistar rats by 60-min occlusion of the middle cerebral artery (MCAO). Brain damage was assessed 24 h after MCAO by T2 MRI. Rats were scanned with C-R-PK11195 and F-GE-180 5 or 6 days after MCAO. Specificity of binding was confirmed by injection of unlabelled R-PK11195 or GE-180 20 min after injection of F-GE-180. In vivo data were confirmed by ex vivo immunohistochemistry for microglial (CD11b) and astrocytic biomarkers (GFAP). Results: F-GE-180 uptake was 24 % higher in the core of the ischaemic lesion and 18 % lower in the contralateral healthy tissue than that of C-R-PK11195 uptake (1.5 ± 0.2-fold higher signal to noise ratio). We confirmed this finding using the simplified reference tissue model (BP = 3.5 ± 0.4 and 2.4 ± 0.5 for F-GE-180 and C-R-PK11195, respectively, with R = 1). Injection of unlabelled R-PK11195 or GE-180 20 min after injection of F-GE-180 significantly displaced F-GE-180 (69 ± 5 % and 63 ± 4 %, respectively). Specificity of the binding was also confirmed by in vitro autoradiography, and the location and presence of activated microglia and infiltrated macrophages were confirmed by immunohistochemistry. Conclusion: The in vivo binding characteristics of F-GE-180 demonstrate a better signal to noise ratio than C-R-PK11195 due to both a better signal in the lesion and lower nonspecific binding in healthy tissue. These results provide evidence that F-GE-180 is a strong candidate to replace C-R-PK11195. [ABSTRACT FROM AUTHOR]

The level of the translocator protein (TSPO) increases dramatically in microglial cells when the cells are activated in response to neuronal injury and insult. The radiotracer [18F]GE-180 binds selectively and with high affinity to TSPO and can therefore be used to measure neuroinflammation in a variety of disease states. An optimized, automated synthesis of [18F]GE-180 has been developed for the GE FASTlab™ synthesizer. The entire process takes place on the single-use cassette. The radiolabelling is performed by nucleophilic fluorination of the S- enantiomer mesylate precursor. The crude product is purified post-radiolabelling using two solid-phase extraction cartridges integrated on the cassette. Experimental design and multivariate data analysis were used to assess the robustness, and critical steps were optimized with respect to efficacy and quality. The average radiochemical yield is 48% (RSD 6%, non-decay corrected), and the synthesis time including purification is approximately 43 min. The radiochemical purity is ≥95% for radioactive concentration ≤1100 MBq/mL. The total amount of precursor-related chemical impurities is 1-2 µg/mL. The use of solid-phase extraction purification results in a robust GMP compliant process with a product of high chemical and radiochemical purity and consistent performance across positron emission tomography (PET) centers. [ABSTRACT FROM AUTHOR]

[ 18 F]GE-180 has been demonstrated to be a promising new positron emission tomography radiotracer for targeting translocator protein. PET imaging of TSPO will enable measurement of neuroinflammation and microglia activity in vivo. The synthetic route used in the initial discovery of GE-180, whilst enabling the rapid evaluation of the structure–activity relationships (SAR) in this molecular class, was not high yielding and not suitable for scale-up. Here we present an optimised route towards GE-180 and the radiolabelling precursor of [ 18 F]GE-180 with significantly improved yields due to a strategy which improves the regioselectivity of the key indole formation step of the synthesis. [ABSTRACT FROM AUTHOR]

Purpose: Tracer kinetic modeling of tissue time activity curves and the individual input function based on arterial blood sampling and metabolite correction is the gold standard for quantitative characterization of microglia activation by PET with the translocator protein (TSPO) ligand 18 F-GE-180. This study tested simplified methods for quantification of 18 F-GE-180 PET., Methods: Dynamic 18 F-GE-180 PET with arterial blood sampling and metabolite correction was performed in five healthy volunteers and 20 liver-transplanted patients. Population-based input function templates were generated by averaging individual input functions normalized to the total area under the input function using a leave-one-out approach. Individual population-based input functions were obtained by scaling the input function template with the individual parent activity concentration of 18 F-GE-180 in arterial plasma in a blood sample drawn at 27.5 min or by the individual administered tracer activity, respectively. The total 18 F-GE-180 distribution volume (V T ) was estimated in 12 regions-of-interest (ROIs) by the invasive Logan plot using the measured or the population-based input functions. Late ROI-to-whole-blood and ROI-to-cerebellum ratio were also computed., Results: Correlation with the reference V T (with individually measured input function) was very high for V T with the population-based input function scaled with the blood sample and for the ROI-to-whole-blood ratio (Pearson correlation coefficient = 0.989 ± 0.006 and 0.970 ± 0.005). The correlation was only moderate for V T with the population-based input function scaled with tracer activity dose and for the ROI-to-cerebellum ratio (0.653 ± 0.074 and 0.384 ± 0.177). Reference V T , population-based V T with scaling by the blood sample, and ROI-to-whole-blood ratio were sensitive to the TSPO gene polymorphism. Population-based V T with scaling to the administered tracer activity and the ROI-to-cerebellum ratio failed to detect a polymorphism effect., Conclusion: These results support the use of a population-based input function scaled with a single blood sample or the ROI-to-whole-blood ratio at a late time point for simplified quantitative analysis of 18 F-GE-180 PET.

Neuroinflammation has been associated with various neurologic diseases, including Alzheimer disease (AD). In AD, the translocator protein 18 kDa (TSPO) is overexpressed in the activated microglia that surround the β-amyloid plaques. In the current longitudinal study using a mouse model of AD, we evaluated the association between β-amyloid deposition and neuroinflammation in AD. Methods: To monitor the longitudinal changes in β-amyloid deposition and neuroinflammation, we used in vivo PET imaging and ex vivo autoradiography with Pittsburgh compound B ( 11 C-PIB) and a TSPO tracer, flutriciclamide ( 18 F-GE-180), in the APP23 mouse model of AD. We also applied immunohistochemistry to study β-amyloid and activated microglia in the mouse brain tissue. Results: From 17 to 26 mo of age, the mice showed robust increased binding of 11 C-PIB with aging in the frontal cortex, parietotemporal cortex, hippocampus, and thalamus whereas the increase in 18 F-GE-180 binding with aging was minimal in areas of early amyloidosis such as the frontal cortex and hippocampus. A clear positive correlation between β-amyloid deposition and neuroinflammation was detected with 11 C-PIB and 18 F-GE-180 only in the parietotemporal cortex and thalamus. Conclusion: The neuroinflammation increase detected with 18 F-GE-180 is less than the increase in amyloidosis detected with 11 C-PIB. Furthermore, binding of 18 F-GE-180 plateaus at an earlier stage of pathogenesis whereas amyloidosis continues to increase. We suggest that TSPO can be a good marker for early pathogenesis detection but not for tracking long-term disease progression., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: The 18-kDa translocator protein (TSPO) has been highlighted as a potential drug target in diverse neurodegenerative diseases because the up-regulation of TSPO in the CNS is related to neuroinflammation. Diverse TSPO ligands are currently in clinical trials or are under development at the preclinical stage for the treatment and/or diagnosis of neurodegenerative processes. These TSPO ligands may shed light on novel therapeutics for neurodegenerative diseases in the near future. Areas covered: This review describes TSPO ligands that have been patented from 2010 to 2015. Numerous indole-derived TSPO ligands will be analyzed on the basis of their TSPO affinities. Furthermore, cholesterol-like compounds and miscellaneous TSPO ligands will be summarized along with their pharmaceutical uses. Expert opinion: Diverse TSPO ligands have demonstrated their biological efficacies in experimental models of neurodegenerative diseases, and some of them are now in clinical trials. The indole-derived TSPO ligands can be highlighted as efficient diagnostic agents because they have high selectivity and affinity for TSPO. Moreover, one potent cholesterol-like TSPO ligand has been described as a neuroprotective compound. Therefore, additional preclinical and clinical studies for highly potent TSPO ligands are recommended for the successful pharmacological application of TSPO ligands.

The level of the translocator protein (TSPO) increases dramatically in microglial cells when the cells are activated in response to neuronal injury and insult. The radiotracer [(18) F]GE-180 binds selectively and with high affinity to TSPO and can therefore be used to measure neuroinflammation in a variety of disease states. An optimized, automated synthesis of [(18) F]GE-180 has been developed for the GE FASTlab™ synthesizer. The entire process takes place on the single-use cassette. The radiolabelling is performed by nucleophilic fluorination of the S- enantiomer mesylate precursor. The crude product is purified post-radiolabelling using two solid-phase extraction cartridges integrated on the cassette. Experimental design and multivariate data analysis were used to assess the robustness, and critical steps were optimized with respect to efficacy and quality. The average radiochemical yield is 48% (RSD 6%, non-decay corrected), and the synthesis time including purification is approximately 43 min. The radiochemical purity is ≥95% for radioactive concentration ≤1100 MBq/mL. The total amount of precursor-related chemical impurities is 1-2 µg/mL. The use of solid-phase extraction purification results in a robust GMP compliant process with a product of high chemical and radiochemical purity and consistent performance across positron emission tomography (PET) centers., (Copyright © 2013 John Wiley & Sons, Ltd.)