An optimized protocol for the radiosynthesis of (–)-[F-18]flubatine permits its application as a new PET radioligand for neuroimaging of alpha4beta2-nAChRs

Objectives:

The alpha4beta2 subtype of nicotinic acetylcholine receptors (nAChRs) is involved in various neurodegenerative diseases. (–)-[F-18]flubatine is a new and promising PET tracer for neuroimaging of alpha4beta2-nAChRs and is currently investigated in a first study in humans. The original radiosynthesis of (–)-[F-18]flubatine was based on the bromo precursor and afforded the product in low yields (~2-3%). Here we present a new high yield radiosynthesis strategy based on an optimised leaving group/ protecting group assembly.

Methods:

A small library of precursors was synthesized containing –Cl, –NO2 and trimethylammonium (TMA) triflate and iodide as leaving groups and ethylcarbamate, Fmoc, Trityl, as well as Boc as protecting groups. [F-18]flubatine, was prepared via a two-step radiosynthesis. In the first step the nucleophilic radiofluorination was investigated. The radiolabelled product was then deprotected to yield the final radiotracer.

Results:

The best radiochemical results were obtained with a TMA iodide precursor containing a Bocprotecting group. Radiolabelling afforded the protected product in yields of 90±5%, with a RCY 70±5% (n=25) and a specific activity >350 GBq/Hmol. The complete deprotection of the Boc-PG succeeded with 1M HCl at 90°C within 5 min. TMA iodide precursors with other PGs led to lower labelling yields and several by-products after deprotection. Analytical and semipreparative HPLC separation protocols were developed using RP18-AQ phases and (–)-[F-18]flubatine was isolated in very high purity. The final product is stable in diluted HCl, NaOH and K2CO3 solutions as well as under physiological conditions.

Conclusions:

An optimized radiosynthesis of (–)-[F-18]flubatine was developed which will allow for an easy and automated radiotracer production applicable for human studies.

Research Support:

The project was supported by the German Federal Ministry of Education and Research (01EZ0820).