In vivo evaluation of six analogs of 11C-ER176 as candidate 18F-labeled radioligands for translocator protein 18 kDa (TSPO)

Abstract Background The translocator protein 18 kDa is recognised as an important biomarker for neuroinflammation due to its soaring expression in microglia. This process is common for various neurological disorders. DPA-714 is a potent TSPO-specific ligand which found its use in Positron Emission Tomography following substitution of fluorine-19 with fluorine-18, a positron-emitting radionuclide. [18F]DPA-714 enables visualisation of inflammatory processes in vivo non-invasively. Radiolabelling of this tracer is well described in literature, including validation for clinical use. Here, we report significant enhancements to the process which resulted in the design of a fully GMP-compliant robust synthesis of [18F]DPA-714 on a popular cassette-based system, Trasis AllinOne, boosting reliability, throughput, and introducing a significant degree of simplicity. Results [18F]DPA-714 was synthesised using the classic nucleophilic aliphatic substitution on a good leaving group, tosylate, with [18F]fluoride using tetraethylammonium bicarbonate in acetonitrile at 100∘C. The process was fully automated on a Trasis AllinOne synthesiser using an in-house designed cassette and sequence. With a relatively small precursor load of 4 mg, [18F]DPA-714 was obtained with consistently high radiochemical yields of 55-71% (n=6) and molar activities of 117-350 GBq/µmol at end of synthesis. With a single production batch, starting with 31-42 GBq of [18F]fluoride, between 13-20 GBq of the tracer can be produced, enabling multi-centre studies. Conclusion To the best of our knowledge, the process presented herein is the most efficient [18F]DPA-714 synthesis, with advantageous GMP compliance. The use of a Trasis AllinOne synthesiser increases reliability and allows rapid training of production staff.

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Novel Pyrazolo[1,5-a]pyrimidines as Translocator Protein 18 kDa (TSPO) Ligands: Synthesis, in Vitro Biological Evaluation, [18F]-Labeling, and in Vivo Neuroinflammation PET Images

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.5b00932 ◽

2015 ◽

Vol 58 (18) ◽

pp. 7449-7464 ◽

Cited By ~ 20

Author(s):

Annelaure Damont ◽

Vincent Médran-Navarrete ◽

Fanny Cacheux ◽

Bertrand Kuhnast ◽

Géraldine Pottier ◽

...

Keyword(s):

Biological Evaluation ◽

Translocator Protein ◽

Translocator Protein 18 Kda

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Voxel-Based Imaging of Translocator Protein 18Kda (TSPO) in High-Resolution PET

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.203 ◽

2013 ◽

Vol 33 (3) ◽

pp. 348-350 ◽

Cited By ~ 9

Author(s):

Ji Hyun Ko ◽

Yuko Koshimori ◽

Romina Mizrahi ◽

Pablo Rusjan ◽

Alan A Wilson ◽

...

Keyword(s):

Relative Equilibrium ◽

Compartment Model ◽

Graphical Analysis ◽

Translocator Protein ◽

Proof Of Concept ◽

Tissue Compartment ◽

Potential Biomarker ◽

Translocator Protein 18 Kda ◽

Significant Attention

In vivo imaging of translocator protein 18 kDa (TSPO) has received significant attention as potential biomarker of microglia activation. Several radioligands have been designed with improved properties. Our group recently developed an 18F-labeled TSPO ligand, [18F]-FEPPA, and confirmed its reliability with a 2-tissue compartment model. Here, we extended, in a group of healthy subjects, its suitability for use in voxel-based analysis with the newly proposed graphical analysis approach, Relative-Equilibrium-Gjedde-Patlak (REGP) plot. The REGP plot successfully replicated the total distribution volumes estimated by the 2-tissue compartment model. We also showed its proof-of-concept in a patient with possible meningioma showing increased [18F]-FEPPA total distribution volume.

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In vivo imaging of neuroinflammation in the rodent brain with [11C]SSR180575, a novel indoleacetamide radioligand of the translocator protein (18 kDa)

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-010-1628-5 ◽

2010 ◽

Vol 38 (3) ◽

pp. 509-514 ◽

Cited By ~ 36

Author(s):

Fabien Chauveau ◽

Hervé Boutin ◽

Nadja Van Camp ◽

Cyrille Thominiaux ◽

Philippe Hantraye ◽

...

Keyword(s):

In Vivo Imaging ◽

Translocator Protein ◽

Rodent Brain ◽

Translocator Protein 18 Kda

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Insights into smouldering MS brain pathology with multimodal diffusion tensor and PET imaging

10.1101/2020.01.09.20017012 ◽

2020 ◽

Author(s):

Svetlana Bezukladova ◽

Jouni Tuisku ◽

Markus Matilainen ◽

Anna Vuorimaa ◽

Marjo Nylund ◽

...

Keyword(s):

White Matter ◽

Pet Imaging ◽

Microglial Activation ◽

Diffusion Tensor ◽

Volume Ratio ◽

Translocator Protein ◽

Control Group ◽

In Vivo Evaluation ◽

Conventional Mri

Objective: To evaluate in vivo the co-occurrence of microglial activation and microstructural white matter damage in multiple sclerosis (MS) brain, and to examine their association with clinical disability. Methods: 18-kDa translocator protein (TSPO) brain PET imaging was performed for evaluation of microglial activation by using the radioligand [11C](R)-PK11195. TSPO-binding was evaluated as the distribution volume ratio (DVR) from dynamic PET images. Diffusion tensor imaging (DTI) and conventional MRI were performed at the same time. Mean fractional anisotropy (FA) and mean (MD), axial (AD) and radial (RD) diffusivities were calculated within the whole normal appearing white matter (NAWM) and segmented NAWM regions appearing normal in conventional MRI. 55 MS patients and 15 healthy controls were examined. Results: Microstructural damage was observed in the NAWM of MS brain. DTI parameters of MS patients were significantly altered in the NAWM, when compared to an age- and sex-matched healthy control group: mean FA was decreased, and MD, AD and RD were increased. These structural abnormalities correlated with increased TSPO binding in the whole NAWM and in the temporal NAWM (p<0.05 for all correlations; p<0.01 for RD in the temporal NAWM). Both compromised WM integrity and increased microglial activation in the NAWM correlated significantly with higher clinical disability measured with expanded disability status scale (EDSS). Conclusions: Widespread structural disruption in the NAWM is linked to neuroinflammation, and both phenomena associate with clinical disability. Multimodal PET and DTI imaging allows in vivo evaluation of widespread MS pathology not visible using conventional MRI.

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Unbinding of Translocator Protein 18 kDa (TSPO) Ligands: From in Vitro Residence Time to in Vivo Efficacy via in Silico Simulations

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.9b00300 ◽

2019 ◽

Vol 10 (8) ◽

pp. 3805-3814 ◽

Cited By ~ 7

Author(s):

Agostino Bruno ◽

Elisabetta Barresi ◽

Nicola Simola ◽

Eleonora Da Pozzo ◽

Barbara Costa ◽

...

Keyword(s):

Residence Time ◽

In Silico ◽

Translocator Protein ◽

In Vivo Efficacy ◽

Translocator Protein 18 Kda

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Insights into disseminated MS brain pathology with multimodal diffusion tensor and PET imaging

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000691 ◽

2020 ◽

Vol 7 (3) ◽

pp. e691 ◽

Cited By ~ 3

Author(s):

Svetlana Bezukladova ◽

Jouni Tuisku ◽

Markus Matilainen ◽

Anna Vuorimaa ◽

Marjo Nylund ◽

...

Keyword(s):

Pet Imaging ◽

Microglial Activation ◽

Diffusion Tensor ◽

Volume Ratio ◽

Translocator Protein ◽

In Vivo Evaluation ◽

Conventional Mri ◽

Disability Status ◽

Distribution Volume Ratio

ObjectiveTo evaluate in vivo the co-occurrence of microglial activation and microstructural white matter (WM) damage in the MS brain and to examine their association with clinical disability.Methods18-kDa translocator protein (TSPO) brain PET imaging was performed for evaluation of microglial activation by using the radioligand [11C](R)-PK11195. TSPO binding was evaluated as the distribution volume ratio (DVR) from dynamic PET images. Diffusion tensor imaging (DTI) and conventional MRI (cMRI) were performed at the same time. Mean fractional anisotropy (FA) and mean (MD), axial, and radial (RD) diffusivities were calculated within the whole normal-appearing WM (NAWM) and segmented NAWM regions appearing normal in cMRI. Fifty-five patients with MS and 15 healthy controls (HCs) were examined.ResultsMicrostructural damage was observed in the NAWM of the MS brain. DTI parameters of patients with MS were significantly altered in the NAWM compared with an age- and sex-matched HC group: mean FA was decreased, and MD and RD were increased. These structural abnormalities correlated with increased TSPO binding in the whole NAWM and in the temporal NAWM (p < 0.05 for all correlations; p < 0.01 for RD in the temporal NAWM). Both compromised WM integrity and increased microglial activation in the NAWM correlated significantly with higher clinical disability measured with the Expanded Disability Status Scale score.ConclusionsWidespread structural disruption in the NAWM is linked to neuroinflammation, and both phenomena associate with clinical disability. Multimodal PET and DTI allow in vivo evaluation of widespread MS pathology not visible using cMRI.

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Translocator Protein (18 kDa) Polymorphism (rs6971) Explains in-vivo Brain Binding Affinity of the PET Radioligand [18F]-FEPPA

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.46 ◽

2012 ◽

Vol 32 (6) ◽

pp. 968-972 ◽

Cited By ~ 79

Author(s):

Romina Mizrahi ◽

Pablo M Rusjan ◽

James Kennedy ◽

Bruce Pollock ◽

Benoit Mulsant ◽

...

Keyword(s):

Binding Affinity ◽

Microglial Activation ◽

Translocator Protein ◽

Time Activity ◽

Genetic Groups ◽

Positron Emission ◽

Translocator Protein 18 Kda ◽

Human Brains ◽

New Generation

[18F]-FEPPA binds to the 18-kDa translocator protein (TSPO) and is used in positron emission tomography (PET) to detect microglial activation. However, quantitative interpretations of the PET signal with new generation TSPO PET radioligands are confounded by large interindividual variability in binding affinity. This presents as a trimodal distribution, reflecting high-affinity binders (HABs), low-affinity binder (LAB), and mixed-affinity binders (MABs). Here, we show that one polymorphism (rs6971) located in exon 4 of the TSPO gene, which results in a nonconservative amino-acid substitution from alanine to threonine (Ala147Thr) in the TSPO protein, predicts [18F]-FEPPA total distribution volume in human brains. In addition, [18F]-FEPPA exhibits clearly different features in the shape of the time activity curves between genetic groups. Testing for the rs6971 polymorphism may allow quantitative interpretation of TSPO PET studies with new generation of TSPO PET radioligands.

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