Synthesis, 18F-Radiolabelling and Biological Characterization of Novel Fluoroalkylated Triazine Derivatives for in Vivo Imaging of Phosphodiesterase 2A in Brain via Positron Emission Tomography

• Published in: Molecules (Basel, Switzerland) Vol. 20; no. 6; pp. 9591 - 9615
• Main Authors: Schröder, Susann, Wenzel, Barbara, Deuther-Conrad, Winnie, Teodoro, Rodrigo, Egerland, Ute, Kranz, Mathias, Scheunemann, Matthias, Höfgen, Norbert, Steinbach, Jörg, Brust, Peter
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26-05-2015; MDPI
• Subjects: Alzheimer's disease; Animals; Autoradiography; Brain; Brain - metabolism; Brain - ultrastructure; Cyclic Nucleotide Phosphodiesterases, Type 2 - antagonists & inhibitors; Cyclic Nucleotide Phosphodiesterases, Type 2 - metabolism; Derivatives; Enzymes; Female; Fluorine Radioisotopes; Humans; Imaging; In vitro testing; Inhibitors; Investigations; Isotope Labeling - methods; Ligands; Mice; micellar HPLC; Neuroimaging - methods; Neurological disorders; PDE2A; Permeability; PET imaging in brain; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - metabolism; Phosphodiesterase Inhibitors - pharmacokinetics; Positron emission; Positron-Emission Tomography; Proteins; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - metabolism; Radiopharmaceuticals - pharmacokinetics; Rats; Rats, Sprague-Dawley; Tomography; Triazines - chemistry; Triazines - metabolism; Triazines - pharmacokinetics; Tumors; Germany; PET imaging in brain; micellar HPLC; Alzheimer’s disease; PDE2A
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules20069591

Phosphodiesterase 2A (PDE2A) is highly and specifically expressed in particular brain regions that are affected by neurological disorders and in certain tumors. Development of a specific PDE2A radioligand would enable molecular imaging of the PDE2A protein via positron emission tomography (PET). Herein we report on the syntheses of three novel fluoroalkylated triazine derivatives (TA2-4) and on the evaluation of their effect on the enzymatic activity of human PDE2A. The most potent PDE2A inhibitors were 18F-radiolabelled ([18F]TA3 and [18F]TA4) and investigated regarding their potential as PET radioligands for imaging of PDE2A in mouse brain. In vitro autoradiography on rat brain displayed region-specific distribution of [18F]TA3 and [18F]TA4, which is consistent with the expression pattern of PDE2A protein. Metabolism studies of both [18F]TA3 and [18F]TA4 in mice showed a significant accumulation of two major radiometabolites of each radioligand in brain as investigated by micellar radio-chromatography. Small-animal PET/MR studies in mice using [18F]TA3 revealed a constantly increasing uptake of activity in the non-target region cerebellum, which may be caused by the accumulation of brain penetrating radiometabolites. Hence, [18F]TA3 and [18F]TA4 are exclusively suitable for in vitro investigation of PDE2A. Nevertheless, further structural modification of these promising radioligands might result in metabolically stable derivatives.