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Purpose: The prototypical TSPO radiotracer (R)-[ 11 C]PK11195 has been used in humans for more than thirty years to visualize neuroinflammation in several pathologies. Alternative radiotracers have been developed to improve signal-to-noise ratio and started to be tested clinically in 2008. Here we examined the scientific value of these "(R)-[ 11 C]PK11195 challengers" in clinical research to determine if they could supersede (R)-[ 11 C]PK11195., Methods: A systematic MEDLINE (PubMed) search was performed (up to end of year 2020) to extract publications reporting TSPO PET in patients with identified pathologies, excluding studies in healthy subjects and methodological studies., Results: Of the 288 publications selected, 152 used 13 challengers, and 142 used (R)-[ 11 C]PK11195. Over the last 20 years, the number of (R)-[ 11 C]PK11195 studies remained stable (6 ± 3 per year), but was surpassed by the total number of challenger studies for the last 6 years. In total, 3914 patients underwent a TSPO PET scan, and 47% (1851 patients) received (R)-[ 11 C]PK11195. The 2 main challengers were [ 11 C]PBR28 (24%-938 patients) and [ 18 F]FEPPA (11%-429 patients). Only one-in-ten patients (11%-447) underwent 2 TSPO scans, among whom 40 (1%) were scanned with 2 different TSPO radiotracers., Conclusions: Generally, challengers confirmed disease-specific initial (R)-[ 11 C]PK11195 findings. However, while their better signal-to-noise ratio seems particularly useful in diseases with moderate and widespread neuroinflammation, most challengers present an allelic-dependent (Ala147Thr polymorphism) TSPO binding and genetic stratification is hindering their clinical implementation. As new challengers, insensitive to TSPO human polymorphism, are about to enter clinical evaluation, we propose this systematic review to be regularly updated (living review)., (© 2021. The Author(s).)

Background: The 5-HT6 receptor is one of the most recently identified serotonin receptors in the central nervous system. Because of its role in memory and cognitive process, this receptor might be implicated in Alzheimer's disease (AD) and associated disorders., Objective: The aim of this study was to investigate the binding of [18F]2FNQ1P, a new specific radiotracer of 5-HT6 receptors, and to quantify 5-HT6 receptor density in caudate nucleus in a population of patients with different AD stages., Methods: Patients were classified according to the "ABC" NIA-AA classification. In vitro binding assays were performed in postmortem brain tissue from the healthy control (HC; n = 8) and severe AD ("High"; n = 8) groups. In vitro quantitative autoradiography was performed in human brain tissue (caudate nucleus) from patients with different stages of AD: HC (n = 15), "Low" (n = 18), "Int" (n = 20), and "High" (n = 15)., Results: In vitro binding assays did not show significant differences for the KD and Bmax parameters between "High" and HC groups. In vitro quantitative autoradiography showed a significant difference between the "High" and HC groups (p = 0.0025). We also showed a progressive diminution in [18F]2FNQ1P specific binding, which parallels 5-HT6 receptors expression, according to increasing AD stage. Significant differences were observed between the HC group and all AD stages combined ("Low", "Intermediate", and "High") (p = 0.011)., Conclusion: This study confirms the interest of investigating the role of 5-HT6 receptors in AD and related disorders. [18F]2FNQ1P demonstrated specific binding to 5-HT6 receptors.

The observation that amyloid radiotracers developed for Alzheimer's disease bind to cerebral white matter paved the road to nuclear imaging of myelin in multiple sclerosis. The lysolecithin (lysophosphatidylcholine (LPC)) rat model of demyelination proved useful in evaluating and comparing candidate radiotracers to target myelin. Focal demyelination following stereotaxic LPC injection is larger than lesions observed in experimental autoimmune encephalitis models and is followed by spontaneous progressive remyelination. Moreover, the contralateral hemisphere may serve as an internal control in a given animal. However, demyelination can be accompanied by concurrent focal necrosis and/or adjacent ventricle dilation. The influence of these side effects on imaging findings has never been carefully assessed. The present study describes an optimization of the LPC model and highlights the use of MRI for controlling the variability and pitfalls of the model. The prototypical amyloid radiotracer [ 11 C]PIB was used to show that in vivo PET does not provide sufficient sensitivity to reliably track myelin changes and may be sensitive to LPC side effects instead of demyelination as such. Ex vivo autoradiography with a fluorine radiotracer should be preferred, to adequately evaluate and compare radiotracers for the assessment of myelin content.

The accumulation of aggregated alpha-synuclein ( α -syn) in multiple brain regions is a neuropathological hallmark of synucleinopathies. Multiple system atrophy (MSA) is a synucleinopathy characterized by the predominant cerebral accumulation of aggregated α -syn as cytoplasmic glial inclusions (CGI). A premortem diagnosis tool would improve early diagnosis and help monitoring disease progression and therapeutic efficacy. One Positron Emission Tomography (PET) study suggested [ 11 C]BF-227 as a promising radiotracer for monitoring intracellular α -syn deposition in MSA patients. We sought to confirm the binding of this radiotracer to α -syn using state-of-the-art autoradiography. Medulla sections were obtained from 9 MSA patients and 9 controls (London Neurodegenerative Diseases Brain Bank). [ 18 F]BF-227, chemically identical to [ 11 C]BF-227, was used at nanomolar concentrations to perform in vitro autoradiography assays. Autoradiograms were superimposed on fluorescent staining from the conformational anti- α -syn antibody 5G4 and quantified after immunofluorescence-driven definition of regions of interest. Autoradiography showed no specific signals in MSA patients in comparison to controls despite widespread pathology detected by immunofluorescence. Autoradiography does not support a significant binding of [ 18 F]BF-227 to CGI at concentrations typically achieved in PET experiments.

Alpha-synuclein (α-syn) aggregation is a neuropathological hallmark of many neurodegenerative diseases, collectively termed synucleinopathies. There is currently no pre-mortem diagnosis tool for these diseases. Although some compounds have been described as potential ligands for α-syn aggregates, no specific PET radiotracer of aggregated α-syn is currently available. Recently, [(18)F]BF227 has been proposed as an α-syn PET radiotracer in the absence of other specific candidates. We proposed here, for the first time, to use this radiotracer in an accelerated mouse model of synucleinopathy presenting α-syn depositions in brainstem and thalamus. Our in vivo and in vitro studies showed that [(18)F]BF227 does not bind to α-syn aggregates. These results highlight the fact that [(18)F]BF227 PET has no suitable characteristics for monitoring this experimental synucleinopathy, justifying the need to develop alternative α-syn PET radiotracers.

Purpose: Neuroinflammation is involved in neurological disorders through the activation of microglial cells. Imaging of neuroinflammation with radioligands for the translocator protein (18 kDa) (TSPO) could prove to be an attractive biomarker for disease diagnosis and therapeutic evaluation. The indoleacetamide-derived 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, SSR180575, is a selective high-affinity TSPO ligand in human and rodents with neuroprotective effects., Methods: Here we report the radiolabelling of SSR180575 with (11)C and in vitro and in vivo imaging in an acute model of neuroinflammation in rats., Results: The image contrast and the binding of [(11)C]SSR180575 are higher than that obtained with the isoquinoline-based TSPO radioligand, [(11)C]PK11195. Competition studies demonstrate that [(11)C]SSR180575 has high specific binding for the TSPO., Conclusion: [(11)C]SSR180575 is the first PET radioligand for the TSPO based on an indoleacetamide scaffold designed for imaging neuroinflammation in animal models and in the clinic.

Purpose: The key role of neuroinflammation in acute and chronic neurological disorders has stimulated the search for specific radiotracers targeting the peripheral benzodiazepine receptor (PBR)/18 kDa translocator protein (TSPO), a hallmark of neuroinflammation. Here we evaluate the new radiotracer for positron emission tomography (PET) [(18)F]PBR111 in a rodent model of acute inflammation and compare it with [(11)C]CLINME, an (11)C-labelled tracer of the same chemical family, and with the isoquinolinic carboxamide [(11)C]PK11195., Methods: We studied radiometabolites by HPLC, in vitro binding by autoradiography and in vivo brain kinetics as well as in vivo specificity of binding using PET imaging., Results: We show that this radiotracer has a high in vitro specificity for PBR/TSPO versus central benzodiazepine receptors, as reflected by the drastic reduction of its binding to target tissue by addition of PK11195 or PBR111, while addition of flumazenil does not affect binding. Only intact [(18)F]PBR111 is detected in brain up to 60 min after i.v. injection, and PET imaging shows an increased uptake in the lesion as compared to the contralateral side as early as 6 min after injection. Administration of an excess of PK11195 and PBR111, 20 min after [(18)F]PBR111 administration, induces a rapid and complete displacement of [(18)F]PBR111 binding from the lesion. Modelling of the PET data using the simplified reference tissue model showed increased binding potential (BP) in comparison to [(11)C]PK11195., Conclusion: [(18)F]PBR111 is a metabolically stable tracer with a high specific in vitro and in vivo binding to TSPO. In addition, considering the longer half-life of (18)F over (11)C, these results support [(18)F]PBR111 as a promising PET tracer of the PBR/TSPO for neuroinflammation imaging.

The peripheral benzodiazepine receptor (PBR) is expressed by microglial cells in many neuropathologies involving neuroinflammation. PK11195, the reference compound for PBR, is used for positron emission tomography (PET) imaging but has a limited capacity to quantify PBR expression. Here we describe the new PBR ligand CLINME as an alternative to PK11195. In vitro and in vivo imaging properties of [(11)C]CLINME were studied in a rat model of local acute neuroinflammation, and compared with the reference compound [(11)C]PK11195, using autoradiography and PET imaging. Immunohistochemistry study was performed to validate the imaging data. [(11)C]CLINME exhibited a higher contrast between the PBR-expressing lesion site and the intact side of the same rat brain than [(11)C]PK11195 (2.14 +/- 0.09 vs. 1.62 +/- 0.05 fold increase, respectively). The difference was due to a lower uptake for [(11)C]CLINME than for [(11)C]PK11195 in the non-inflammatory part of the brain in which PBR was not expressed, while uptake levels in the lesion were similar for both tracers. Tracer localization correlated well with that of activated microglial cells, demonstrated by immunohistochemistry and PBR expression detected by autoradiography. Modeling using the simplified tissue reference model showed that R(1) was similar for both ligands (R(1) approximately 1), with [(11)C]CLINME exhibiting a higher binding potential than [(11)C]PK11195 (1.07 +/- 0.30 vs. 0.66 +/- 0.15). The results show that [(11)C]CLINME performs better than [(11)C]PK11195 in this model. Further studies of this new compound should be carried out to better define its capacity to overcome the limitations of [(11)C]PK11195 for PBR PET imaging.

Unlabelled: The induction of neuroinflammatory processes, characterized by upregulation of the peripheral benzodiazepine receptor (PBR) expressed by microglial cells, is well correlated with neurodegenerative diseases and with acute neuronal loss. The continually increasing incidence of neurodegenerative diseases in developed countries has become a major health problem, for which the development of diagnostic and follow-up tools is required. Here we investigated a new PBR ligand suitable for PET to monitor neuroinflammatory processes as an indirect hallmark of neurodegeneration., Methods: We compared PK11195, the reference compound for PBR binding sites, with the new ligand DPA-713 (N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl]acetamide), using a small-animal dedicated PET camera in a model of neuroinflammation in rats. Seven days after intrastriatal injection of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), a PET scan was performed using (11)C-PK11195 or (11)C-DPA-713. Immunohistochemistry for neuronal (NeuN), astrocyte (glial fibrillary acidic protein), and microglial (CD11) specific markers as well as (3)H-PK11195 autoradiographic studies were then correlated with the imaging data., Results: Seven days after a unilateral injection of AMPA in the striatum, (11)C-DPA-713 exhibits a better contrast between healthy and damaged brain parenchyma than (11)C-PK11195 (2.5-fold +/- 0.14 increase vs. 1.6-fold +/- 0.05 increase, respectively). (11)C-DPA-713 and (11)C-PK11195 exhibit similar brain uptake in the ipsilateral side, whereas, in the contralateral side, (11)C-DPA-713 uptake was significantly lower than (11)C-PK11195. Modeling of the data using the simplified reference tissue model shows that the binding potential was significantly higher for (11)C-DPA-713 than for (11)C-PK11195., Conclusion: (11)C-DPA-713 displays a higher signal-to-noise ratio than (11)C-PK11195 because of a lower level of unspecific binding that is likely related to the lower lipophilicity of (11)C-DPA-713. Although further studies in humans are required, (11)C-DPA-713 represents a suitable alternative to (11)C-PK11195 for PET of PBR as a tracer of neuroinflammatory processes induced by neuronal stress.