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In this study we synthesized four different 18 F-labeling precursors for the visualization of the monoamino oxidase A using harmol derivatives. Whereas two are for prosthetic group labeling using [ 18 F]fluoro- d 2 -methyl tosylate and 2-[ 18 F]fluoroethyl-tosylate, the other three precursors are for direct nucleophilic 18 F-labeling. Additionally the corresponding reference compounds were synthesized. The syntheses of [ 18 F]fluoro- d 2 -methyl-harmol and 2-[ 18 F]fluoroethyl-harmol were carried out using harmol as starting material. For direct nucleophilic 18 F-labeling of the tracers carrying oligoethyled spacers (PEG), a toluenesulfonyl leaving group was employed. The radiolabeling, purification and formulation for each tracer was optimized and evaluated in vitro and in vivo. Stability tests in human serum showed that all tracers were stable over the observation period of 60 min. μPET studies using of the synthesized tracers revealed that the tracers carrying PEG spacers showed no sufficient brain uptake. Consequently, the 18 F-fuoro alkylated tracers [ 18 F]fluoro- d 2 -methyl-harmol and 2-[ 18 F]fluoroethyl-harmol were further evaluated showing SUVs in the brain of 1.0 ± 0.2 g/mL and 3.4 ± 0.5 g/mL after 45 min, respectively. In blockade studies the selectivity and specificity of both tracers were demonstrated. However, for [ 18 F]fluoro- d 2 -methyl-harmol a rapid washout from the brain was also observed. In vitro binding assays revealed that 2-[ 18 F]fluoroethyl-harmol (IC 50 = 0.54 ± 0.06 nM) has a higher affinity than the 18 F-fluoro- d 2 -methylated ligand (IC 50 = 12.2 ± 0.6 nM), making 2-[ 18 F]fluoroethyl-harmol superior to the other evaluated compounds and a promising tracer for PET imaging of the MAO A. [ABSTRACT FROM AUTHOR]

The compound screening was initiated with a direct staining assay to identify compounds binding to Tau aggregates and not Abeta plaques using human brain sections derived from late stage Alzheimer's disease donors. The binding of Tau aggregate selective compounds was then quantitatively assessed with human brain derived paired helical filaments utilizing the label-free Back Scattering Interferometry assay. In vivo biodistribution experiments of selected fluorine-18 labeled compounds were performed in mice to assess brain uptake, brain washout, and defluorination. Compound 11 emerged as the most promising candidate, displaying high in vitro binding affinity and selectivity to neurofibrillary tangles. Fluorine-18 labeled compound 11 showed high brain uptake and rapid washout from the mouse brain with no observed bone uptake. Furthermore, compound 11 was able to detect Tau aggregates in tauopathy brain sections from corticobasal degeneration, progressive supranuclear palsy, and Pick's disease donors. Thus, 2-(4-(2-fluoroethoxy)piperidin-1-yl)-9-methyl-9 H -pyrrolo[2,3- b :4,5- c ']dipyridine (PI-2014 , compound 11) was selected for characterization in a first-in-human study. Image 1 • Hit to lead optimization resulted in the discovery of compound 11 (PI-2014). • PI-2014 showed selective binding to Tau over Abeta, a-synuclein and TDP-43. • PI-2014 showed binding to Tau aggregates in AD, CBD, PSP, and Pick's disease. • PET studies of 18 F]PI-2014 in mouse and non-human primate showed high brain uptake. [ABSTRACT FROM AUTHOR]