Radiosynthesis and Biological Investigation of a Novel Fluorine-18 Labeled Benzoimidazotriazine- Based Radioligand for the Imaging of Phosphodiesterase 2A with Positron Emission Tomography.

Ritawidya Ritawidya,Scheunemann Scheunemann,Deuther-Conrad Deuther-Conrad,Ludwig Ludwig,Toussaint Toussaint,Teodoro Teodoro,Wenzel Wenzel,Kranz Kranz,Brust Brust,Dukic-Stefanovic Dukic-Stefanovic

doi:10.3390/molecules24224149

Abstract

A specific radioligand for the imaging of cyclic nucleotide phosphodiesterase 2A (PDE2A) via positron emission tomography (PET) would be helpful for research on the physiology and disease-related changes in the expression of this enzyme in the brain. In this report, the radiosynthesis of a novel PDE2A radioligand and the subsequent biological evaluation were described. Our prospective compound 1-(2-chloro-5-methoxy phenyl)-8-(2-fluoropyridin-4-yl)-3- methylbenzo[e]imidazo[5,1-c][1,2,4]triazine, benzoimidazotriazine (BIT1) (IC50 PDE2A = 3.33 nM; 16-fold selectivity over PDE10A) was fluorine-18 labeled via aromatic nucleophilic substitution of the corresponding nitro precursor using the K[18F]F-K2.2.2-carbonate complex system. The new radioligand [18F]BIT1 was obtained with a high radiochemical yield (54 ± 2%, n = 3), a high radiochemical purity (≥99%), and high molar activities (155–175 GBq/μmol, n = 3). In vitro autoradiography on pig brain cryosections exhibited a heterogeneous spatial distribution of [18F]BIT1 corresponding to the known pattern of expression of PDE2A. The investigation of in vivo metabolism of [18F]BIT1 in a mouse revealed sufficient metabolic stability. PET studies in mouse exhibited a moderate brain uptake of [18F]BIT1 with a maximum standardized uptake value of ~0.7 at 5 min p.i. However, in vivo blocking studies revealed a non-target specific binding of [18F]BIT1. Therefore, further structural modifications are needed to improve target selectivity.

Highlights

The cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes catalyzing the hydrolysis of the intracellular secondary messengers, cyclic adenosine monophosphate and cyclic guanosine monophosphate [1,2,3]
We very The recently reported on the synthesis and inhibitory potency of nine new fluorinated synthesis of the reference compound BIT1 has been reported previously
As depicted in Scheme 1, 5 was prepared in four steps starting from the BIT key intermediate for 18Miyaura

Summary

Introduction

The cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes catalyzing the hydrolysis of the intracellular secondary messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) [1,2,3]. The dual-substrate enzyme PDE2A is abundantly expressed in brain, in particular, in caudate, nucleus accumbens, cortex, hippocampus [3,8,9], amygdala [10,11], substantia nigra, as well as olfactory tubercle [11,12], while the expression in the midbrain, hindbrain, and cerebellum is comparatively low [8,11,12] This specific distribution indicates a role of PDE2A in the modulation of complex neuronal processes, such as learning, concentration, memory, emotion, depression, anxiety, and CNS related disorder [10,13,14]. PDE2A inhibition has the potential to prolong the duration of cAMP- and cGMP-dependent signaling pathways, eventually improving neural plasticity and memory function [3,13,17]

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Conclusion