Exploring diagnostic and therapeutic opportunities of LAT1-selective PET imaging in glioblastoma.

Promovendus/a
Jeroen Verhoeven
Faculteit
Faculteit Farmaceutische Wetenschappen
Vakgroep
Vakgroep Farmaceutische Analyse
Curriculum
Master of science in pharmaceutical care, Universiteit Gent, 2014 Bachelor of science in pharmaceutical sciences, Universiteit Gent, 2012 Sciences-Mathematics, Immaculata instituut De Panne, 2009
Academische graad
Doctor in de farmaceutische wetenschappen
Taal proefschrift
Engels
Vertaling titel
Exploratie van de diagnostische en therapeutische mogelijkheden van LAT1-selectieve PET beeldvorming bij glioblastoma.
Promotor(en)
Prof. Dr., Filip De Vos, UGent-Farmaceutische Analyse - Prof. dr., Ingeborg Goethals, UZ Gent
Examencommissie
Prof. dr., Bruno De Geest, UGent-Geneesmiddelenleer - Prof. dr., Koen Raemdonck, UGent-Geneesmiddelenleer - Dr., Julie Bolcaen, iThema Labs South Africa - Prof. dr., Tom Boterberg, UZ Gent - Dr., Ken Kersemans, UZ Gent - Prof. dr., Christan Vanhove, UGent-Faculteit ingenieurswetenschappen

Korte beschrijving

The aim of this dissertation is twofold. Firstly, we are interested in evaluating the feasibility of a preclinical glioblastoma (GB) rodent model for the application of positron emission tomography (PET) based dose painting and subsequent evaluation of treatment outcome. The second aim is to develop a 18F-labeled phenylalanine analogue for PET imaging that has more favorable affinity and specificity for the L type amino acid 1 transporter (LAT1) than the standard amino acid tracer [18F]FET. Therefore, in the first experimental chapter a PET-guided radiation therapy experiment is set up targeting the most metabolically active regions using [18F]FET, or radioresistant/hypoxic regions using [18F]FAZA in addition to MRI. Preclinical dose painting by contours of GB is feasible, although very time consuming. Certain advancements are needed to obtain a better tumor delineation, such as more tumor-specific PET tracers. In the following chapters different derivatives of phenylalanine were synthesized and evaluated in vitro. Of the compounds tested, 2-FELP exhibits the most favorable affinity towards the LAT1 transporter. Using a straightforward nucleophilic substitution reaction, the radiosynthesis of 2-[18F]FELP is carried out and implemented on a Synthra RN plus module. 2-[18F]FELP remains stable in formulation and inhibition assays using different inhibitors (BCH, MeAiB, JPH203) reveals an improved selectivity for LAT1 when compared to [18F]FET. The final chapter investigates how these improved characteristics are translated in vivo in comparison to [18F]FET and [18F]FDG by assessing the uptake in GB, radiation necrosis and inflammation. In conclusion, we developed 2-[18F]FELP for GB imaging with greater in vitro affinity and specificity for the LAT1 transporter than the clinically used amino acid tracer [18F]FET. These improved characteristics are translated in vivo, resulting in a superior capability to differentiate GB from inflammation and radiation necrosis.

Praktisch

Datum
Maandag 17 augustus 2020, 18:00
Livestream
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