Abstract
1023
Objectives: In oncological applications the folate receptor (FR) is a well-known target. In the diagnostic field different folates have been developed to image FR-positive tumors while for therapy folates have been derivatized in order to treat malignancies related to FR overexpression. The pteroic acid part of folic acid is responsible for FR binding. By detaching glutamate binding affinity and hydrophilicity were reduced. In order to avoid those drawbacks an oligoethylene spacer and DOTA were incorporated. So far only SPECT-radionuclides have been integrated in the development of radiopteroates. Goal of this work was the development and subsequent evaluation of a radiopteroate suitable for FR imaging via PET.
Methods: The synthesis started with the coupling of tetraethylene glycol (TEG) and DOTA(Tris)- ethylamine (EA) in order to obtain DOTA(Tris)-EA-TEG-NH2-CBZ. Deprotection of CBZ was performed by palladium catalyzed hydrogenation and the obtained compound was subsequently coupled to protected pteroic acid (4-[(2-amino-4-oxo-1H-pteridin-6-yl)methylamino]benzoic acid). After a final deprotection DOTA-EA-TEG-pteroic acid was labelled with gallium-68. The in vivo behavior was studied using nude mice bearing human KB cell line xenografts and healthy mice in PET/CT-scans. For the evaluation FR knockdown cells were generated through lentiviral infection of shRNA against FR.
Results: A displacement study using tritiated folic acid was performed and indicated a good affinity to the FR. In in vivo experiments a specific uptake of 68Ga-DOTA-EA-TEG-pteroate in FR(+)-tumors was observed which could be blocked with co-administration of excess folic acid. No uptake was visible in FR knockdown tumors. Overall, it demonstrated a favorable pharmacokinetic profile with fast renal clearance.
Conclusion: A new 68Ga-labelled pteroate was obtained in four steps and further evaluated in vitro and in vivo. The results showed a FR-specific tumor uptake. Research Support: