WORK PACKAGE 3

Synthesis of probes for detection of NIND by PET and SPECT

Fourteen INMiND partner institutions from eleven countries (Australia, Belgium, Denmark, Finland, France, Germany, Hungary, Italy, Sweden, The Netherlands, United Kingdom) are involved in the research activities of this work package. Leader of this work package is Bert WINDHORST, head of the Radiochemistry Section at the Department of Radiology & Nuclear Medicine, VU University Medical Centre Amsterdam (The Netherlands).

The main objectives of this work package are:

  • WP3 aims to develop and evaluate suitable imaging biomarkers (radiotracers) for early and non-invasive diagnosis and therapy follow-up in NIND by means of PET and SPECT.
  • These PET and SPECT biomarkers will be designed in close collaboration with WP1/2, in order to define the best possible biological targets in NIND, selected from the various inflammatory targets.
  • In addition, WP3 will work closely together with WP5/6/8/9 in order to evaluate and validate newly developed biomarkers and to use the results of WP5/6/8/9 to possibly improve the imaging properties of identified biomarker candidates.
  • In this translational and reverse-translational role of WP3 (situated between WP1/2 and WP5/6/8/9) optimal circumstances are created to push the imaging biomarkers into human application in order to enable assessment of effects of therapy in patients with NIND in vivo.
  • WP3 will exploit the strategic advantage of radiotracers with regards to the short period between preclinical validation and clinical application through the microdosing paradigm.

WP3 Related papers


2018

Beckers L, Ory D, Geric I, Declercq L, Koole M, Kassiou M, Bormans G, Baes M. Increased expression of translocator protein (TSPO) marks pro-inflammatory microglia but does not predict neurodegeneration. Mol Imaging Biol. 2018;20(1):94-102.
Read full paper via ZENODO

Janssen B, Vugts DJ, Wilkinson SM, Ory D, Chalon S, Hoozemans JJM, Schuit RC, Beaino W, Kooijman EJM, van den Hoek J, Chishty M, Domene A, Van der Perren A, Villa A, Maggi A, Molenaar GT, Funke U, Shevchenko RV, Baekelandt V, Bormans G, Lammertsma A, Kassiou M, Windhorst AD. Identification of the allosteric P2X7 receptor antagonist [11C]SMW139 as a PET tracer of microglial activation. Sci Rep. 2018;8(1):6580.
Read abstract via ZENODO

Janssen B, Vugts DJ, Windhorst AD, Mach RH. PET Imaging of Microglial Activation - Beyond Targeting TSPO. Molecules 2018; 23:607.
Read full paper via ZENODO

Kellermayer MSZ, Vörös Z, Csík G, Herényi L. Forced phage uncorking: viral DNA ejection triggered by  mechanical sensitive switch. Nanoscale. 2018;10(4):1898-1904.
Read abstract via PUBMED


2017

Ahamed M, Attili B, van Veghela D, Ooms M, Berben P, Celen S, Koole M, Declercq L, Savinainen J, Laitinen J, Verbruggen A, Bormans G. Synthesis and preclinical evaluation of [11C]MA-PB-1 for in vivo imaging of brain monoacylglycerol lipase (MAGL). Eur J Med Chem. 2017;136:104-113.
Read abstract via ZENODO

Beaino W, Janssen B, Kooij G, van der Pol SMA, van Het Hof B, van Horssen J, Windhorst AD, de Vries HE. Purinergic receptors P2Y12R and P2X7R: potential targets for PET imaging of microglia phenotypes in multiple sclerosis. J Neuroinflammation. 2017;14(1):259.
Read full paper via ZENODO

Cacheux F, Médran-Navarrete V, Dollé F, Marguet F, Puech F, Damont A. Synthesis and in vitro characterization of novel fluorinated derivatives of the translocator protein 18 kDa ligand CfO-DPA-714. Eur J Med Chem. 2017;125:346-359.
Read abstract via ZENODO

Caillé F, Cacheux F, Peyronneau MA, Jego B, Jaumain E, Pottier G, Ullmer C, Grether U, Winkeler A, Dollé F,  Damont A, Kuhnast B. From structure-activity relationships on thiazole derivatives to the in vivo evaluation of a new radiotracer for cannabinoid subtype 2 PET imaging. Mol Pharm. 2017;14(11):4064-4078.
Read full paper via ZENODO

Hugenberg V, Wagner S, Kopka K, Schäfers M, Schuit RC, Windhorst AD, Hermann S. Radiolabeled Selective Matrix Metalloproteinase 13 (MMP-13) Inhibitors: (Radio)Syntheses and in Vitro and First in Vivo Evaluation. J Med Chem. 2017;60(1):307-321.
Read full paper via ZENODO

Keller T, Krzyczmonik A, Forsback S, López Picón FR, Kirjavainen AK, Takkinen J, Rajander J, Cacheux F, Damont A, Dollé F, Rinne JO, Haaparanta-Solin M, Solin O. Radiosynthesis and Preclinical Evaluation of [18F]F-DPA, a Novel Pyrazolo[1,5a]pyrimidine Acetamide TSPO Radioligand, in healthy Sprague Dawley rats. Mol Imaging Biol. 2017;19(5):736-745.
Read full paper via ZENODO

O'Brien-Brown J, Jackson A, Reekie TA, Barron ML, Werry EL, Schiavini P, McDonnell M, Munoz L, Wilkinson S, Noll B, Wang S, Kassiou M. Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists. Eur J Med Chem. 2017;130:433-439.
Read full paper via ZENODO

Sokias R, Werry EL, Chua SW, Reekie TA, Munoz L, Wong ECN, Itner LM, Kassiou M. Determination and reduction of translocator protein (TSPO) ligand rs6971 discrimination. Med. Chem. Commun. 2017;8:202-210.
Read full paper via ZENODO

Struys T, Govaerts K, Oosterlinck W, Casteels C, Bronckaers A, Koole M, Van Laere K, Herijgers P, Lambrichts I, Himmelreich U, Dresselaers T. In vivo evidence for long-term vascular remodeling resulting from chronic cerebral hypoperfusion in mice. J Cereb Blood Flow Metab 2017; 37(2): 726-739.
Read abstract via PUBMED

Vörös Z, Csík G, Herényi L, Kellermayer MS. Stepwise reversible nanomechanical buckling in a viral capsid. Nanoscale. 2017;9(3):1136-1143.
Read abstract via PUBMED

Werry EL, King VA, Barron ML, Banister SD, Sokias R, Kassiou M. Derivatives of the pyrazolo[1,5-a]pyrimidine acetamide DPA-713 as translocator protein (TSPO) ligands and pro-apoptotic agents in human glioblastoma. Eur J Pharm Sci. 2017;96:186-192.
Read abstract via ZENODO

Wilkinson SM, Barron ML, O'Brien-Brown J, Janssen B, Stokes L, Werry EL, Chishty M, Skarratt KK, Ong JA, Hibbs DE, Vugts DJ, Fuller S, Windhorst AD, Kassiou M. Pharmacological evaluation of novel bioisosteres of an adamantanyl benzamide P2X7 receptor antagonist. ACS Chem Neurosci. 2017;8(11):2374-2380.
Read abstract via ZENODO

Willekens SM, Van Weehaeghe D, Van Damme P, Van Laere K. Positron emission tomography in amyotrophic lateral sclerosis: Towards targeting of molecular pathological hallmarks. Eur J Nucl Med Mol Imaging. 2017;44(3):533-547.
Read abstract via ZENODO

Wong ECN, Reekie TA, Werry EL, O'Brien-Brown J, Bowyer SL, Kassiou M. Pharmacological evaluation of a novel series of urea, thiourea and guanidine derivatives as P2X7 receptor antagonists. Bioorg Med Chem Lett. 2017;27(11):2439-2442.
Read abstract via ZENODO


2016

Janssen B, Vugts DJ, Funke U, Molenaar GT, Kruijer PS, van Berckel BN, Lammertsma AA, Windhorst AD. Imaging of neuroinflammation in Alzheimer's disease, multiple sclerosis and stroke: Recent developments in positron emission tomography. Biochim Biophys Acta. 2016;1862(3):425-41.
Read full paper via ZENODO

Nag S, Fazio P, Lehmann L, Kettschau G, Heinrich T, Thiele A, Svedberg M, Amini N, Leesch S, Catafau A, Hannestad J, Varrone A, Halldin C. In Vivo/In Vitro Characterisation of a Novel MAO-B Inhibitor Radioligand, Fluorine-18 Labeled Deuterated Fluorodeprenyl (18F-Fluorodeprenyl-D2). J Nucl Med. 2016;57(2):315-20.
Read abstract via ZENODO

Ory D, Postnov A, Koole M, Celen S, de Laat B, Verbruggen A, Van Laere K, Bormans G, Casteels C. Quantification of TSPO overexpression in a rat model of local neuroinflammation induced by intracerebral injection of LPS by the use of [18F]DPA-714 PET. Eur J Nucl Med Mol Imaging. 2016;43(1):163-72.
Read full paper via ZENODO

Rotstein BH, Liang SH, Placzek MS, Hooker JM, Gee AD, Dollé F, Wilson AA, Vasdev N. 11C-Carbonyl (11C=O) bonds made easily for Positron Emission Tomography radiopharmaceuticals. Chem Soc Rev. 2016;45(17):4708-26.
Read full paper via ZENODO


2015

Banister SD, Beinat C, Wilkinson SM, Shen B, Bartoli C, Selleri S, Da Pozzo E, Martini C, Chin FT, Kassiou M. Ether analogues of DPA-714 with subnanomolar affinity for the translocator protein (TSPO). Eur J Med Chem. 2015;93:392-400.
Read full paper via ZENODO

Banister SD, Stuart J, Conroy T, Longworth M, Manohar M, Beinat C, Wilkinson SM, Kevin RC, Hibbs DE, Glass M, Connor M, McGregor IS, Kassiou M. Structure–activity relationships of synthetic cannabinoid designer drug RCS-4 and its regioisomers and C4 homologues. Forensic Toxicol. 2015;33(2):355-366.
Read full paper via ZENODO

Banister SD, Stuart J, Kevin RC, Edington A, Longworth M, Wilkinson SM, Beinat C, Buchanan AS, Hibbs DE, Glass M, Connor M, McGregor IS, Kassiou M. Effects of bioisosteric fluorine in synthetic cannabinoid designer drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135. ACS Chem Neurosci. 2015;6(8):1445-58.
Read full paper via ZENODO

Coliva A, Monterisi C, Apollaro A, Gatti D, Penso M, Gianolli L, Perani D, Gilardi MC, Carpinelli A. Synthesis optimization of 2-(4-N-[11C]methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB), β-amyloid PET imaging tracer for Alzheimer's disease diagnosis. Appl Radiat Isot. 2015;105:66-71.
Read abstract via ZENODO

Damont A, Garcia-Argote S, Buisson DA, Rousseau B, Dollé F. Efficient tritiation of the translocator protein (18 kDa) selective ligand DPA-714. J Labelled Comp Radiopharm. 2015;58(1):1-6.
Read abstract via ZENODO

Damont A, Marguet F, Puech F, Dollé F. Synthesis and in vitro characterization of novel fluorinated derivatives of the TSPO 18 kDa ligand SSR180575. Eur J Med Chem. 2015;101:736-45.
Read abstract via ZENODO

Damont A, Medran-Navarrete V, Cacheux F, Kuhnast B, Pottier G, Bernards N, Marguet F, Puech F, Boisgard R, Dollé F. Novel pyrazolo[1,5-a]pyrimidines as translocator protein 18 kDa (TSPO) ligands: Synthesis, in vitro biological evaluation, [18F]-labelling and in vivo neuroinflammation PET images. J Med Chem. 2015;58(18):7449-64.
Read full paper via ZENODO

Farde L. Spotlight: TSPO binding may also represent ‘resting’ microglia. Clin Transl Imaging. 2015;3(6):491-492.
Read full paper via ZENODO

Narlawar R, Werry EL, Scarf AM, Hanani R, Chua SW, King VA, Barron ML, Martins RN, Ittner LM, Rendina LM, Kassiou M. First Demonstration of Positive Allosteric-like Modulation at the Human Wild Type Translocator Protein (TSPO). J Med Chem. 2015;58(21):8743-9.
Read full paper via ZENODO


2014

Janssen B, Vugts DJ, Funke U, Spaans A, Schuit RC, Kooijman E, Rongen M, Perk LR, Lammertsma AA, Windhorst AD. Synthesis and initial preclinical evaluation of the P2X7 receptor antagonist [11C]A-740003 as a novel tracer of neuroinflammation. J Labelled Comp Radiopharm. 2014;57(8):509-16.
Read abstract via ZENODO

Médran-Navarrete V, Bernards N, Kuhnast B, Damont A, Pottier G, Peyronneau MA, Kassiou M, Marguet F, Puech F, Boisgard R, Dollé F. [18F]DPA-C5yne, a novel fluorine-18-labeled analogue of DPA-714: Radiosynthesis and preliminary evaluation as a radiotracer for imaging neuroinflammation with PET. J Labelled Comp Radiopharm. 2014;57(6):410-8.
Read abstract via ZENODO

Médran-Navarrete V, Damont A, Peyronneau MA, Kuhnast B, Bernards N, Pottier G, Marguet F, Puech F, Boisgard R, Dollé F. Preparation and evaluation of novel pyrazolo[1,5-a]pyrimidine acetamides, closely related to DPA-714, as potent ligands for imaging the TSPO 18 kDa with PET. Bioorg Med Chem Lett. 2014;24(6):1550-6.
Read abstract via ZENODO

Ooms M, Rietjens R, Rangarajan JR, Vunckx K, Valdeolivas S, Maes F, Himmelreich U, Fernandez-Ruiz J, Bormans G, Van Laere K, Casteels C. Early decrease of type 1 cannabinoid receptor binding and phosphodiesterase 10A activity in vivo in R6/2 Huntington mice. Neurobiol Aging. 2014;35(12):2858-69.
Read full paper via ZENODO

Ory D, Celen S, Verbruggen A, Bormans G. PET radioligands for in vivo visualization of neuroinflammation. Curr Pharm Des. 2014;20(37):5897-913.
Read full paper via ZENODO

Wilkinson S, Gunosewoyo H, Barron M, Boucher, A, McDonnell M, Turner P, Morrison D, Bennett M, McGregor I, Rendina L, Kassiou M. The first CNS-active carbarone: A novel P2X7 receptor antagonist with antidepressant activity. ACS Chem Neurosci. 2014;5(5):335-9.
Read full paper via ZENODO


2013

Banister SD, Wilkinson SM, Longworth M, Stuart J, Apetz N, English K, Brooker L, Goebel C, Hibbs DE, Glass M, Connor M, McGregor IS, Kassiou M. The synthesis and pharmacological evaluation of adamantane-derived indoles: Cannabimimetic drugs of abuse. ACS Chem Neurosci. 2013;4(7):1081-92.
Read abstract via ZENODO

Damont A, Roeda D, Dollé F. The potential of carbon-11 and fluorine-18 chemistry: Illustration through the development of PET-radioligands targeting the TSPO 18 kDa. J Labelled Comp Radiopharm. 2013;56(3-4):96-104.
Read abstract via ZENODO

Funke U, Vugts DJ, Janssen B, Spaans A, Kruijer PS, Lammertsma AA, Perk LR, Windhorst AD. 11C-labeled and 18F-labeled PET ligands for subtype-specific imaging of histamine receptors in the brain. J Label Compd Radiopharm. 2013;56:120–9.
Read abstract via ZENODO

Nag S, Kettschau G, Heinrich T, Varrone A, Lehmann L, Gulyas B, Thiele A, Keller É, Halldin C. Synthesis and biological evaluation of novel propargyl amines as potential fluorine-18 labeled radioligands for detection of MAO-B activity. Bioorg Med Chem. 2013;21(1):186-95.
Read abstract via ZENODO

Nag S, Lehmann L, Kettschau G, Toth M, Heinrich T, Thiele A, Varrone A, Halldin C. Development of a novel fluorine-18 labeled deuterated fluororasagiline ([18F]fluororasagiline-D2) radioligand for PET studies of monoamino oxidase B (MAO-B). Bioorg Med Chem. 2013;21(21):6634-41.
Read abstract via ZENODO


2012

Jacobs AH, Tavitian B; INMiND consortium. Noninvasive molecular imaging of neuroinflammation. J Cereb Blood Flow Metab. 2012;32(7):1393-415.
Read full paper via ZENODO

INMiND Office
European Institute for Molecular Imaging (EIMI) Waldeyerstr. 15
· 48149 Münster
Tel: +49 251 83 49300 · Fax: +49 251 83 49313
E-Mail: