Abstract B32: Synthetic routes to 18F-labeled gemcitabine and related 2'-fluoronucleosides.
Authors: Meyer Jan-Philip 
Published: August 2014

Gemcitabine (2,2′-difluoro-2′-deoxycytidine, dFdC) is an established chemotherapeutic agent used in the treatment of various carcinomas such as lung, breast, bladder and especially pancreatic cancer (1)]. However, its general application and bioavailability is compromised due to both poor cell uptake and rapid metabolism by gut and liver cytidine deaminase (CD)(2). An 18F-gemcitabine positron emission tomography (PET) probe would allow tracking of this important drug on its biomolecular pathways in vivo. Treatment improvement and a deeper understanding of cancer biochemistry are some possible beneficial outcomes. The half-life of 18F (110 minutes) and GMP regulations restrict synthetic and purification procedures to a short period of time. Thus, the main focus of this project is the development of new powerful strategies to introduce fluorine at the latest stage of the chemical synthesis into appropriate nucleoside precursors. In order to approach the synthetic target molecule dFdC, proof-of-principle studies on more straightforward synthetic targets including 1-(2′-deoxy-2′-[18F]fluoro-beta-D-arabinofuranosyl)uracil (18F-FAU) and 1-(2′-deoxy-2′-[18F]fluoro-beta-D-arabinofuranosyl)cytidine (18F-FAC) are carried out first. An appropriate precursor synthesis for 2′-stereoselective radiofluorination is followed by the introduction of the 18F-isotope under recently developed conditions (3,4). Radiochemical syntheses are carried out using an Eckert & Ziegler module system. The obtained radio-nucleosides are confirmed by radio-HPLC and subsequent radio-ESI-MS at the Wales Research & Diagnostic Positron Emission Tomography Imaging Centre (PETIC) located at Heath Hospital in Cardiff. Several fluorination methods and nucleoside precursors were tested under different conditions. The 2′-fluorinated arabinonucleoside 2′-deoxy-2′-fluorouracil (FAU), which was considered as a rapidly accessible 2′-fluorinated uracil-based dFdC analogue was successfully synthesized in our laboratory. Here, a protected mesylate precursor was treated with tetrabutylammonium fluoride (TBAF) under anhydrous conditions at reflux temperatures in acetonitrile to give the fluorinated nucleoside FAU in acceptable overall yields after subsequent deprotection. This procedure was successfully used as a template method to obtain 18F-FAU and 18F-FIAU in a new and efficient way in good radiochemical yields (14-17%, decay-corrected). This knowledge is now being transferred to the late-stage synthesis of the more challenging and biologically relevant cytidine-based radiotracer 18F-FAC at PETIC which has potential application in the imaging of neurogenesis. Additionally, the successful radiochemical synthesis of the PET probe FIAU will enable its potential applications in reporter-gene imaging developments. Considering the final target, the development of an appropriate fluorination precursor for the radiosynthesis of 18F-Gemcitabine will be investigated mainly based on the results obtained from the mono-fluoro model studies.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B32.

Citation Format: Jan-Philip Meyer. Synthetic routes to 18F-labeled gemcitabine and related 2'-fluoronucleosides. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B32.