Radiosynthesis and preclinical evaluation of an 18F-labeled tri-azolopyridopyrazine-based inhibitor for neuroimaging of the phosphodiesterase 2A (PDE2A)


Radiosynthesis and preclinical evaluation of an 18F-labeled tri-azolopyridopyrazine-based inhibitor for neuroimaging of the phosphodiesterase 2A (PDE2A)

Wenzel, B.; Fritzsche, S. R.; Toussaint, M.; Briel, D.; Kopka, K.; Brust, P.; Scheunemann, M.; Deuther-Conrad, W.

The cyclic nucleotide phosphodiesterase 2A is an intracellular enzyme which hydrolyzes the secondary messengers cAMP and cGMP and therefore plays an important role in signaling cas-cades. A high expression in distinct brain areas as well as in cancer cells makes PDE2A an inter-esting therapeutic and diagnostic target for neurodegenerative and neuropsychiatric diseases as well as for cancer. Aiming at a specific imaging of this enzyme in the brain with positron emis-sion tomography (PET), a new triazolopyridopyrazine-based derivative (11) was identified as a potent PDE2A inhibitor (IC50, PDE2A = 1.99 nM; IC50, PDE10A ~ 2000 nM) and has been radiofluorinated for biological evaluation. In vitro autoradiographic studies revealed that [18F]11 binds with high affinity and excellent specificity towards PDE2A in the rat brain. For the PDE2A-rich region nu-cleus caudate and putamen an apparent KD value of 0.24 nM and an apparent Bmax value of 16 pmol/mg protein were estimated. In vivo PET-MR studies in rat showed a moderate brain uptake of [18F]11 with a highest standardized uptake value (SUV) of 0.97. However, no considerable en-richment in PDE2A-specific regions in comparison to a reference region was detectable (SUVcau-date putamen = 0.51 vs. SUVcerebellum = 0.40 at 15 min p.i.). Furthermore, metabolism studies revealed a considerable uptake of radiometabolites of [18F]11 in the brain (66% parent fraction at 30 min p.i.). Altogether, despite the low specificity and the blood-brain barrier crossing of radiometab-olites observed in vivo, [18F]11 is a valuable imaging probe for the in vitro investigation of PDE2A in the brain and has potential as a lead compound for further development of a PDE2A-specific PET ligand for neuroimaging.

Keywords: PDE2A inhibitor; triazolopyridopyrazine; fluorine-18; small animal PET-MR; autoradiography; in vivo metabolism

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Publ.-Id: 35082