Investigation of an 18F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2A

Abstract

Specific radioligands for in vivo visualization and quantification of cyclic nucleotide phosphodiesterase 2A (PDE2A) by positron emission tomography (PET) are increasingly gaining interest in brain research. Herein we describe the synthesis, the 18F-labelling as well as the biological evaluation of our latest PDE2A (radio-)ligand 9-(5-Butoxy-2-fluorophenyl)-2-(2-([18F])fluoroethoxy)-7-methylimidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine (([18F])TA5). It is the most potent PDE2A ligand out of our series of imidazopyridotriazine-based derivatives so far (IC50 hPDE2A = 3.0 nM; IC50 hPDE10A > 1000 nM). Radiolabelling was performed in a one-step procedure starting from the corresponding tosylate precursor. In vitro autoradiography on rat and pig brain slices displayed a homogenous and non-specific binding of the radioligand. Investigation of stability in vivo by reversed-phase HPLC (RP-HPLC) and micellar liquid chromatography (MLC) analyses of plasma and brain samples obtained from mice revealed a high fraction of one main radiometabolite. Hence, we concluded that [18F]TA5 is not appropriate for molecular imaging of PDE2A neither in vitro nor in vivo. Our ongoing work is focusing on further structurally modified compounds with enhanced metabolic stability.

PET Imaging of the Adenosine A2A Receptor in the Rotenone-Based Mouse Model of Parkinson’s Disease with [18F]FESCH Synthesized by a Simplified Two-Step One-Pot Radiolabeling Strategy

“…Notably and to the best of our knowledge, the formation of brain-penetrating radiometabolites of [ 18 F]FESCH has not been regarded before. Based on our experiences with radiotracers bearing a [ 18 F]fluoroethoxy moiety [34,35] [36,37], which are able to cross the blood-brain barrier [38][39][40][41].…”

Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors

“…Two fluoroalkyl derivatives, TA3 and TA4 (Figure 1), demonstrated high affinity towards PDE2A with 28-fold and 125-fold selectivity over PDE10A, respectively [15,21]. More recently, we gained a further improvement in terms of in vitro PDE2A binding via replacement of the 1-methoxy in TA1 by 1-(2-fluoroethoxy), resulting in the compound TA5 , (Figure 1) [15,21,22]. However, after successful 18 F-labeling, the obtained tracers, [ 18 F] TA3 and [ 18 F] TA4 , did not entirely succeed and were proven to be suitable only for in vitro autoradiographic PDE2A imaging.…”

“…However, after successful 18 F-labeling, the obtained tracers, [ 18 F] TA3 and [ 18 F] TA4 , did not entirely succeed and were proven to be suitable only for in vitro autoradiographic PDE2A imaging. Beyond that, [ 18 F] TA5 failed to demonstrate specific binding in vitro [22]. The formation of brain-penetrating radiometabolites due to the O-defluoroalkylation limited their application for in vivo PDE2A imaging.…”

“…The formation of brain-penetrating radiometabolites due to the O-defluoroalkylation limited their application for in vivo PDE2A imaging. Therefore, further structural modifications of tricyclic lead are inevitably required to allow appropriate in vivo PDE2A imaging [21,22]. A further tracer, [ 18 F] AQ28A , obtained as a developmental compound from our PDE10 program ( AQ28A , Figure 1), was proven to be sufficiently metabolically stable and to enable in vivo imaging of PDE10A in rodents by PET [24].…”

“…As part of our ongoing commitment in 18 F-PET tracer development devoted to PDE imaging (2A, 5A, and 10A) [21,22,24,29], we focused on Benzoimidazotriazine (BIT) as the scaffold, which differs in a benzo ring formally replacing the pyrido ring of our hitherto investigated TA compounds. Because of our findings from AQ28A , we felt encouraged to combine a 2-fluorpyridine moiety as a fluorine-bearing group with structural features required for PDE2A binding (Figure 2).…”