In vivo evaluation of pegylated [¹⁸F]harmine derivatives: Selective reversible MAO-A inhibitors

Objectives The monoamine oxidase A (MAO-A) is responsible for the oxidation of amines from endogenous and exogenous sources. Main substrates are serotonin, dopamine and norepinephrine. Several ¹¹C-labeled MAO-A inhibitors for molecular imaging have been developed, e.g. [¹¹C]harmine has been already used in animal or competition studies in humans. To overcome the limitation of carbon-11, with its half-life of 20.3 min Blom and co-workers synthesized ¹⁸F-labeled harmine derivatives and investigated the in vitro behavior. Our aim was to investigate the in vivo behavior of these compounds.

Methods The fluorine-18 labeling of the precursors was performed at the hydroxyl group of harmol. Whilst three of the compounds also contained PEG-spacers of different length and a tosyl group for ¹⁸F-direct fluorination, the fourth compound was synthesized via ¹⁸F-fluoroethylation of harmol and all were evaluated in µPET studies.

Results We synthesized four ¹⁸F-fluorinated radiotracers, three via direct labeling and one via labeling with 2-[¹⁸F]fluoroethyl tosylate. After optimization of the reaction conditions radiochemical yields (RCY) of 30-45% in case of the direct labeling and 80% in case of the labeling with the prosthetic group were obtained. The in vivo behavior of all compounds was examined in µPET studies with rats, which showed that the pegylated compounds did not cross the Blood Brain Barrier (BBB). Thereforere blocking studies with the superior compound were performed to determine the specificity, which showed a high specificity and also allowed the visualization of MAO-A rich regions like nucleolus coeruleus or thalamus.

Conclusions Four harmine derivatives were labeled with fluorine-18 and their RCY increased by using a µwave-supported synthesis during direct labeling. µPET studies in rats were performed with all compounds, revealing that only the ¹⁸F-fluorethylated compound was able to cross the BBB and blocking experiments with the ¹⁸F-fluorethylated compound were done, which showed a high MAO-A selectivity