Bio

Bio


During his Ph.D. training, Dr. van der Wildt developed PET tracers for in vivo imaging of active tissue transglutaminase at the department of Radiology and Nuclear Medicine at the VU University Medical Center Amsterdam, the Netherlands. He was responsible for the development of novel small molecule inhibitors, development of novel radiolabeling strategies and the in vivo evaluation of the novel PET ligands. His efforts resulted in the first tissue transglutaminase PET tracers reported to date. Following up on his Ph.D research project Berend continued working as a post-doctoral researcher at the Department of Radiology and Nuclear Medicine at the VU University Medical Center Amsterdam, where he was involved in a project that assisted a pharmaceutical company in clinical development of a tissue transglutaminase inhibitor using a PET ligand that he developed during the PhD project. Currently, Dr. van der Wildt has joined the Chin lab at Stanford University where he is responsible for chemical synthesis towards precursors and reference compounds, carbon-11 and fluorine-18 radiochemistry, and execution of preclinical imaging studies with our team.

Professional Education


  • Master of Science, Universiteit Utrecht (2012)
  • Doctor of Philosophy, Vrije Universiteit Amsterdam (2017)
  • Bachelor of Chemistry, Universiteit Utrecht (2012)

Publications

All Publications


  • In vivo evaluation of two tissue transglutaminase PET tracers in an orthotopic tumour xenograft model EJNMMI RESEARCH van der Wildt, B., Wilhelmus, M. M., Beaino, W., Kooijman, E. M., Schuit, R. C., Bol, J. M., Breve, J. P., Pasternack, R., Lammertsma, A. A., Windhorst, A. D., Drukarch, B. 2018; 8: 39

    Abstract

    The protein cross-linking enzyme tissue transglutaminase (TG2; EC 2.3.2.13) is associated with the pathogenesis of various diseases, including cancer. Recently, the synthesis and initial evaluation of two high-potential radiolabelled irreversible TG2 inhibitors were reported by us. In the present study, these two compounds were evaluated further in a breast cancer (MDA-MB-231) tumour xenograft model for imaging active tissue transglutaminase in vivo.The metabolic stability of [11C]1 and [18F]2 in SCID mice was comparable to the previously reported stability in Wistar rats. Quantitative real-time polymerase chain reaction analysis on MDA-MB-231 cells and isolated tumours showed a high level of TG2 expression with very low expression of other transglutaminases. PET imaging showed low tumour uptake of [11C]1 (approx. 0.5 percentage of the injected dose per gram (%ID/g) at 40-60 min p.i.) and with relatively fast washout. Tumour uptake for [18F]2 was steadily increasing over time (approx. 1.7 %ID/g at 40-60 min p.i.). Pretreatment of the animals with the TG2 inhibitor ERW1041E resulted in lower tumour activity concentrations, and this inhibitory effect was enhanced using unlabelled 2.Whereas the TG2 targeting potential of [11C]1 in this model seems inadequate, targeting of TG2 using [18F]2 was achieved. As such, [18F]2 could be used in future studies to clarify the role of active tissue transglutaminase in disease.

    View details for DOI 10.1186/s13550-018-0388-2

    View details for Web of Science ID 000433306300001

    View details for PubMedID 29802556

    View details for PubMedCentralID PMC5970127

  • Strategies towards in vivo imaging of active transglutaminase type 2 using positron emission tomography AMINO ACIDS van der Wildt, B., Lammertsma, A. A., Drukarch, B., Windhorst, A. D. 2017; 49 (3): 585–95

    Abstract

    Transglutaminase type 2 (TG2) is increasingly linked to the pathogenesis of several diseases, such as celiac disease, cancer, and fibrotic and neurodegenerative diseases. In parallel with becoming an attractive target for therapy, interest in the development of compounds for in vivo imaging of TG2 is rising. Such imaging biomarkers might assist in clarifying the role of TG2 in pathology and in monitoring TG2 inhibition in vivo and thus assist in drug development. In this review, the latest results together with various strategies in TG2 PET tracer development are discussed, including radiolabelling of irreversible and reversible active-site inhibitors, as well as allosteric inhibitors, acyl-donor and acyl-acceptor substrates, and anti-TG2 monoclonal antibodies.

    View details for DOI 10.1007/s00726-016-2288-y

    View details for Web of Science ID 000395866200015

    View details for PubMedID 27380031

    View details for PubMedCentralID PMC5332496

  • Development of fluorine-18 labeled peptidic PET tracers for imaging active tissue transglutaminase NUCLEAR MEDICINE AND BIOLOGY van der Wildt, B., Wilhelmus, M. M., Kooijman, E. M., Jongenelen, C. M., Schuit, R. C., Buechold, C., Pasternack, R., Lammertsma, A. A., Drukarch, B., Windhorst, A. D. 2017; 44: 90–104

    Abstract

    The protein-protein crosslinking activity of the enzyme tissue transglutaminase (TG2; EC 2.3.2.13) is associated with the pathogenesis of various diseases, including celiac disease, lung-, liver- and kidney fibrosis, cancer and neurodegenerative diseases. This study aims at developing a TG2 PET tracer based on the peptidic irreversible TG2 inhibitor Z006.Initially, the carbon-11 labeling of Z006 at the diazoketone position was explored. Subsequently, a set of analogues that allow for fluorine-18 labeling was synthesized. Two potent analogues, 6f and 6g, were radiolabeled with fluorine-18 and biodistribution and metabolite analysis in Wistar rats was performed. The identity of the main metabolite of [18F]6g was elucidated using LC-MS/MS. In vitro binding to isolated TG2 and in vitro autoradiography on MDA-MB-231 breast cancer tissue using [18F]6g was performed.[18F]6f and [18F]6g were obtained in 20 and 9% yields, respectively. Following administration to healthy Wistar rats, rapid metabolism of both tracers was observed. Remarkably, full conversion to just one single metabolite was observed for one of the tracers, [18F]6g. By LC-MS/MS analysis this metabolite was identified as C-terminally saponified [18F]6g. This metabolite was also found to be a potent TG2 inhibitor in vitro. In vitro binding to isolated TG2 and in vitro autoradiography on MDA-MB-231 tumor sections using [18F]6g demonstrated high specific and selective binding of [18F]6g to active TG2.Whereas based on the intensive metabolism [18F]6f seems unsuitable as a TG2 PET tracer, the results warrant further evaluation of [18F]6gin vivo.

    View details for DOI 10.1016/j.nucmedbio.2016.10.002

    View details for Web of Science ID 000390836100009

    View details for PubMedID 27837727

  • Development of carbon-11 labeled acryl amides for selective PET imaging of active tissue transglutaminase NUCLEAR MEDICINE AND BIOLOGY van der Wildt, B., Wilhelmus, M. M., Bijkerk, J., Haveman, L. F., Kooijman, E. M., Schuit, R. C., Bol, J. M., Jongenelen, C. M., Lammertsma, A. A., Drukarch, B., Windhorst, A. D. 2016; 43 (4): 232–42

    Abstract

    Tissue transglutaminase (TG2) is a ubiquitously expressed enzyme capable of forming metabolically and mechanically stable crosslinks between the γ-carboxamide of a glutamine acyl-acceptor substrate and the ε-amino functionality of a lysine acyl-donor substrate resulting in protein oligomers. High TG2 crosslinking activity has been implicated in the pathogenesis of various diseases including celiac disease, cancer and fibrotic and neurodegenerative diseases. Development of a PET tracer specific for active TG2 provides a novel tool to further investigate TG2 biology in vivo in disease states. Recently, potent irreversible active site TG2 inhibitors carrying an acrylamide warhead were synthesized and pharmacologically characterized.Three of these inhibitors, compound 1, 2 and 3, were successfully radiolabeled with carbon-11 on the acrylamide carbonyl position using a palladium mediated [(11)C]CO aminocarbonylation reaction. Ex vivo biodistribution and plasma stability were evaluated in healthy Wistar rats. Autoradiography was performed on MDA-MB-231 tumor sections.[(11)C]1, -2 and -3 were obtained in decay corrected radiochemical yields of 38-55%. Biodistribution showed low uptake in peripheral tissues, with the exception of liver and kidney. Low brain uptake of <0.05% ID/g was observed. Blood plasma analysis demonstrated that [(11)C]1 and [(11)C]2 were rapidly metabolized, whereas [(11)C]3 was metabolized at a more moderate rate (63.2 ± 6.8 and 28.7 ± 10.8% intact tracer after 15 and 45 min, respectively). Autoradiography with [(11)C]3 on MDA-MB-231 tumor sections showed selective and specific binding of the radiotracer to the active state of TG2.Taken together, these results identify [(11)C]3 as the most promising of the three compounds tested for development as PET radiotracer for the in vivo investigation of TG2 activity.

    View details for DOI 10.1016/j.nucmedbio.2016.01.003

    View details for Web of Science ID 000375239900002

    View details for PubMedID 27067043

  • [C-11]Sorafenib: Radiosynthesis and preclinical evaluation in tumor-bearing mice of a new TKI-PET tracer NUCLEAR MEDICINE AND BIOLOGY Poot, A. J., van der Wildt, B., Stigter-van Walsum, M., Rongen, M., Schuit, R. C., Hendrikse, N., Eriksson, J., van Dongen, G. S., Windhorst, A. D. 2013; 40 (4): 488–97

    Abstract

    Tyrosine kinase inhibitors (TKIs) like sorafenib are important anticancer therapeutics with thus far limited treatment response rates in cancer patients. Positron emission tomography (PET) could provide the means for selection of patients who might benefit from TKI treatment, if suitable PET tracers would be available. The aim of this study was to radiolabel sorafenib (1) with carbon-11 and to evaluate its potential as TKI-PET tracer in vivo.Synthetic methods were developed in which sorafenib was labeled at two different positions, followed by a metabolite analysis in rats and a PET imaging study in tumor-bearing mice.[methyl-(11)C]-1 and [urea-(11)C]-1 were synthesized in yields of 59% and 53%, respectively, with a purity of >99%. The identity of the products was confirmed by coinjection on HPLC with reference sorafenib. In an in vivo metabolite analysis [(11)C]sorafenib proved to be stable. The percentage of intact product in blood-plasma after 45 min was 90% for [methyl-(11)C]-1 and 96% for [urea-(11)C]-1, respectively. Due to the more reliable synthesis, further research regarding PET imaging was performed with [methyl-(11)C]-1 in nude mice bearing FaDu (head and neck cancer), MDA-MB-231 (breast cancer) or RXF393 (renal cancer) xenografts. Highest tracer accumulation at a level of 2.52 ± 0.33%ID/g was observed in RXF393, a xenograft line extensively expressing the sorafenib target antigen Raf-1 as assessed by immunohistochemistry.In conclusion, we have synthesized [(11)C]sorafenib as PET tracer, which is stable in vivo and has the capability to be used as PET tracer for imaging in tumor-bearing mice.

    View details for DOI 10.1016/j.nucmedbio.2013.02.002

    View details for Web of Science ID 000325842800009

    View details for PubMedID 23522977

  • Tissue transglutaminase colocalizes with extracellular matrix proteins in cerebral amyloid angiopathy NEUROBIOLOGY OF AGING de Jager, M., van der Wildt, B., Schul, E., Bol, J. M., van Duinen, S. G., Drukarch, B., Wilhelmus, M. M. 2013; 34 (4): 1159–69

    Abstract

    Cerebral amyloid angiopathy (CAA) is a key histopathological hallmark of Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). CAA is characterized by amyloid-beta (Aβ) depositions and remodeling of the extracellular matrix (ECM) in brain vessels and plays an important role in the development and progression of both AD and HCHWA-D. Tissue transglutaminase (tTG) modulates the ECM by molecular cross-linking of ECM proteins. Here, we investigated the distribution pattern, cellular source, and activity of tTG in CAA in control, AD, and HCHWA-D cases. We observed increased tTG immunoreactivity and colocalization with Aβ in the vessel wall in early stage CAA, whereas in later CAA stages, tTG and its cross-links were present in halos enclosing the Aβ deposition. In CAA, tTG and its cross-links at the abluminal side of the vessel were demonstrated to be either of astrocytic origin in parenchymal vessels, of fibroblastic origin in leptomeningeal vessels, and of endothelial origin at the luminal side of the deposited Aβ. Furthermore, the ECM proteins fibronectin and laminin colocalized with the tTG-positive halos surrounding the deposited Aβ in CAA. However, we observed that in situ tTG activity was present throughout the vessel wall in late stage CAA. Together, our data suggest that tTG and its activity might play a differential role in the development and progression of CAA, possibly evolving from direct modulation of Aβ aggregation to cross-linking of ECM proteins resulting in ECM restructuring.

    View details for DOI 10.1016/j.neurobiolaging.2012.10.005

    View details for Web of Science ID 000314708000017

    View details for PubMedID 23122413

  • Spacer Effects on in vivo Properties of DOTA-Conjugated Dimeric [Tyr3] Octreotate Peptides Synthesized by a "Cu-I-Click" and "Sulfo-Click" Ligation Method CHEMBIOCHEM Yim, C., van der Wildt, B., Dijkgraaf, I., Joosten, L., Eek, A., Versluis, C., Rijkers, D. S., Boerman, O. C., Liskamp, R. J. 2011; 12 (5): 750–60

    Abstract

    We report on the SSTR2-binding properties of a series of four dimeric [Tyr3]octreotate analogues with different spacer lengths (nine, 19, 41, and 57 atoms) between the peptides. Two analogues (9 and 57 atoms) were selected as precursors for the design, synthesis, and biological evaluation of DOTA-conjugated dimeric [Tyr3]octreotate analogues for tumor targeting. These compounds were synthesized by using a two-stage click ligation procedure: a Cu(I) -catalyzed 1,3-dipolar cycloaddition ("copper-click" reaction) and a thio acid/sulfonyl azide amidation ("sulfo-click" reaction). The IC(50) values of these DOTA-conjugated [Tyr3]octreotate analogues were comparable, and internalization studies showed that the nine-atom (111) In-DOTA-labeled [Tyr3]octreotate dimer had rapid and high receptor binding. Biodistribution studies with BALB/c nude mice bearing subcutaneous AR42J tumors showed that the (111) In-labeled [Tyr3]octreotate dimer (nine atoms) had a high tumor uptake at 1 h p.i. (38.8 ± 8.3 % ID g(-1) ), and excellent tumor retention at 4 h p.i. (40.9 ± 2.5 % ID g(-1) ). However, the introduction of the extended hydrophilic 57 atoms spacer led to rapid clearance from the circulation; this limited tumor accumulation of the radiotracer (21.4 ± 4.9 % ID g(-1) at 1 h p.i.). These findings provide important insight on dimerization and spacer effects on the in vivo properties of DOTA-conjugated [Tyr3]octreotate dimers.

    View details for DOI 10.1002/cbic.201000639

    View details for Web of Science ID 000288563000015

    View details for PubMedID 21328514