Glial Activation in the Early Stages of Brain Metastasis: TSPO as a Diagnostic Biomarker

O’Brien, Emma R.; Kersemans, Veerle; Tredwell, Matthew; Checa, Begoña; Serres, Sébastien; Soto, Manuel Sarmiento; Gouverneur, Véronique; Leppert, David; Anthony, Daniel C.; Sibson, Nicola R.

doi:10.2967/jnumed.113.127449

Cited by 41 publications

(34 citation statements)

References 38 publications

(50 reference statements)

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“…In addition, the location of TSPO on the outer mitochondrial membrane makes it an attractive and readily accessible target for low molecular weight molecules. As a result, numerous TSPO-specific ligands have been developed and radiolabeled for use in positron emission tomography (PET) [4] and single photon emission computed tomography [5]. One of the most significant ligands for TSPO is the isoquinolinecarboxamide PK11195 ( N -butan-2-yl-1-(2-chlorophenyl)- N -methylisoquinoline-3-carboxamide).…”

Section: Introductionmentioning

confidence: 99%

Radiosynthesis and Preclinical Evaluation of [18F]F-DPA, A Novel Pyrazolo[1,5a]pyrimidine Acetamide TSPO Radioligand, in Healthy Sprague Dawley Rats

et al. 2017

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PurposeMany neurological conditions result in the overexpression of the translocator protein 18 kDa (TSPO), today recognized as a biomarker for microglial activation and neuroinflammation imaging. The pyrazolo[1,5-a]pyrimidine acetamides are a particularly attractive class of TSPO-specific ligands, prompting the development of several positron emission tomography (PET) radiotracers. This includes F-DPA, a recently reported fluorinated ligand (K i = 1.7 nM), wherein the fluorine atom is directly linked to the phenyl moiety without the presence of an alkyl or alkoxy spacer chain. Reported here is the preparation of [18F]F-DPA using [18F]Selectfluor bis(triflate) and the preliminary evaluation of [18F]F-DPA in healthy rats. Its metabolic profile and biodistribution in rats are compared with that of [18F]DPA-714, a closely related structure.Procedures[18F]F-DPA was synthesized by electrophilic fluorination using [18F]Selectfluor bis(triflate), [18F]DPA-714 was synthesized by conventional nucleophilic fluorination. The biodistribution of both radiotracers was compared in Sprague Dawley rats. Radiometabolites of both radiotracers in plasma and brain homogenates were analyzed by radioTLC.ResultsThe radiochemical yield of [18F]F-DPA was 15 ± 3 % and the specific activity was 7.8 ± 0.4 GBq/μmol. The radiochemical purity exceeded 99 %. The in vivo time activity curves of [18F]F-DPA demonstrate rapid entry into the brain and a concentration equilibrium at 20–30 min after injection. The metabolic profiles at 90 min after radiotracer injection in the plasma show that unchanged [18F]F-DPA and [18F]DPA-714 account for 28.3 ± 6.4 and 11.1 ± 2.6 % of the remaining radioactivity, respectively. In the brain, unchanged [18F]F-DPA accounts for 93.5 ± 2.8 % of the radioactivity; whereas for [18F]DPA-714, this value is 53.6 ± 1.6 %.Conclusions[18F]Selectfluor bis(triflate) was successfully used to label F-DPA with fluorine-18. The labeling position on the aromatic moiety imparts a higher stability compared to [18F]DPA-714 with regard to in vivo metabolism. [18F]F-DPA is a promising new radiotracer and warrants further investigation in animal models of disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s11307-016-1040-z) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Radiosynthesis and Preclinical Evaluation of [18F]F-DPA, A Novel Pyrazolo[1,5a]pyrimidine Acetamide TSPO Radioligand, in Healthy Sprague Dawley Rats

et al. 2017

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“…To achieve this, we utilised a previously validated model of direct tumour cell injection into the brain parenchyma [25]. We achieved a single focal area of metastatic growth, which exhibited similar growth patterns to those observed following haematogenous dissemination to the brain (Supplementary Figure S6), and corresponding patterns of CAM expression [3].…”

Section: Discussionmentioning

confidence: 99%

Disruption of tumour-host communication by downregulation of LFA-1 reduces COX-2 and e-NOS expression and inhibits brain metastasis growth

et al. 2016

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Over 20% of cancer patients will suffer metastatic spread to the brain, and prognosis remains poor. Communication between tumour cells and host tissue is essential during metastasis, yet little is known of the processes underlying such interactions in the brain.Here we test the hypothesis that cross-talk between tumour cells and host brain cells, through tumour cell leukocyte function associated protein-1 (LFA-1), is critical in metastasis development. Temporal expression of LFA-1 and its major ligand intercellular adhesion molecule-1 (ICAM-1) was determined in two different mouse models of brain metastasis. Marked upregulation of both proteins was found, co-localising with astrocytes, microglia and tumour cells themselves. Silencing of LFA-1 expression in MDA231Br-GFP cells prior to intracerebral injection resulted in > 70% reduction in tumour burden compared to control MDA231Br-GFP cells (p < 0.005, n = 5). Subsequent qRT-PCR analysis of brain tissue revealed significant reductions in COX-2, VEGF and eNOS from host brain tissue, but not tumour cells, in mice injected with LFA-1 knockdown cells (p < 0.0001, n = 5). Finally, expression of both LFA-1 and ICAM-1 was demonstrated in human brain metastasis samples.The results of this study suggest LFA-1 as a new target in brain metastasis therapy and highlight the potential synergy with current anti-COX-2 and anti-NOS therapies.

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“…Given the dependency on myeloid and natural killer (NK) cells to control the dissemination of tumor cells Sceneay et al, 2012;Teng et al, 2011), these metastatic tumor models serve as valuable tool for evaluating immunotherapy that could target these immune subsets. In some cases, to model brain metastases, tumor cell lines may also be intracerebral/intracardially injected into mice (Connell et al, 2013;O'Brien et al, 2014). In addition, under specific experimental conditions, a small number of tumor cell lines are capable of forming spontaneous metastases.…”

Section: Transplantable Tumor Modelsmentioning

confidence: 99%

Mouse Models of Tumor Immunotherapy

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Thomas

et al. 2016

Advances in Immunology

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Glial Activation in the Early Stages of Brain Metastasis: TSPO as a Diagnostic Biomarker

Cited by 41 publications

References 38 publications

Radiosynthesis and Preclinical Evaluation of [18F]F-DPA, A Novel Pyrazolo[1,5a]pyrimidine Acetamide TSPO Radioligand, in Healthy Sprague Dawley Rats

Radiosynthesis and Preclinical Evaluation of [18F]F-DPA, A Novel Pyrazolo[1,5a]pyrimidine Acetamide TSPO Radioligand, in Healthy Sprague Dawley Rats

Disruption of tumour-host communication by downregulation of LFA-1 reduces COX-2 and e-NOS expression and inhibits brain metastasis growth

Mouse Models of Tumor Immunotherapy

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