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

Jeroen Verhoeven
Faculteit Farmaceutische Wetenschappen
Vakgroep Farmaceutische Analyse
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
Vertaling titel
Exploratie van de diagnostische en therapeutische mogelijkheden van LAT1-selectieve PET beeldvorming bij glioblastoma.
Prof. Dr., Filip De Vos, UGent-Farmaceutische Analyse - Prof. dr., Ingeborg Goethals, UZ Gent
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.


Maandag 17 augustus 2020, 18:00
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