Synthesis and preclinical evaluation of an 18 F labeled PDE7 inhibitor for PET neuroimaging

Thomae, David; Servaes, Stijn; Vázquez, Naiara; wyffels, Leonie; Dedeurwaerdere, Stefanie; Veken, Pieter Van der; Joossens, Jurgen; Augustyns, Koen; Stroobants, Sigrid; Staelens, Steven

doi:10.1016/j.nucmedbio.2015.07.007

Cited by 12 publications

(22 citation statements)

References 25 publications

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“…The formation of brain penetrable radiometabolites on the basis of O -dealkylation was already observed for a PDE2 ligand recently developed in our group [ 30 ] and for other ligands bearing fluoroalkoxy side chains bound on an aromatic ring [ 40 , 41 ]. By contrast, also several comparable radiotracers are described which resist to this specific metabolism over a certain time span which would be sufficient for a PET scan [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 78%

Development of a New Radiofluorinated Quinoline Analog for PET Imaging of Phosphodiesterase 5 (PDE5) in Brain

et al. 2016

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Phosphodiesterases (PDEs) are enzymes that play a major role in cell signalling by hydrolysing the secondary messengers cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) throughout the body and brain. Altered cyclic nucleotide-mediated signalling has been associated with a wide array of disorders, including neurodegenerative disorders. Recently, PDE5 has been shown to be involved in neurodegenerative disorders such as Alzheimer’s disease, but its precise role has not been elucidated yet. To visualize and quantify the expression of this enzyme in brain, we developed a radiotracer for specific PET imaging of PDE5. A quinoline-based lead compound has been structurally modified resulting in the fluoroethoxymethyl derivative ICF24027 with high inhibitory activity towards PDE5 (IC50 = 1.86 nM). Radiolabelling with fluorine-18 was performed by a one-step nucleophilic substitution reaction using a tosylate precursor (RCY(EOB) = 12.9% ± 1.8%; RCP > 99%; SA(EOS) = 70–126 GBq/μmol). In vitro autoradiographic studies of [18F]ICF24027 on different mouse tissue as well as on porcine brain slices demonstrated a moderate specific binding to PDE5. In vivo studies in mice revealed that [18F]ICF24027 was metabolized under formation of brain penetrable radiometabolites making the radiotracer unsuitable for PET imaging of PDE5 in brain.

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Section: Discussionmentioning

confidence: 78%

Development of a New Radiofluorinated Quinoline Analog for PET Imaging of Phosphodiesterase 5 (PDE5) in Brain

et al. 2016

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“…In 2015, Thomae et al [121,122] reported on the development of the first two radiolabeled derivatives for that purpose, [ 18 F] 20 ([ 18 F]MICA-003) and [ 11 C] 21 ([ 11 C]MICA-005), based on a series of spiroquinazolinones as potent dual PDE7A/B inhibitors, like compound 19 [123] (Figure 4).…”

Section: Pde7 Radioligandsmentioning

confidence: 99%

“…The spirocyclic compounds 20 and 21 are of high inhibitory potencies towards PDE7 with IC 50 values of 17.0 nM and 1.7 nM, respectively [121,122]. The 18 F-labeled analogue [ 18 F] 20 has been prepared by nucleophilic aliphatic substitution of the tosylate group of the corresponding precursor using K + /[ 18 F]F − /K 2.2.2 -carbonate complex (Scheme 8).…”

Section: Pde7 Radioligandsmentioning

confidence: 99%

“…The 18 F-labeled analogue [ 18 F] 20 has been prepared by nucleophilic aliphatic substitution of the tosylate group of the corresponding precursor using K + /[ 18 F]F − /K 2.2.2 -carbonate complex (Scheme 8). A two-step procedure has been performed for the radiosynthesis of [ 11 C] 21 by methylation of the tetrazole precursor with [ 11 C]methyl triflate under basic conditions (Scheme 9) [121,122]. Biodistribution studies with [ 18 F] 20 in mice revealed a high brain uptake (4%–5%ID/g) at 5 min post injection besides the highest accumulation of this radioligand in heart (10%–11%ID/g) [122].…”

Section: Pde7 Radioligandsmentioning

confidence: 99%

“…A two-step procedure has been performed for the radiosynthesis of [ 11 C] 21 by methylation of the tetrazole precursor with [ 11 C]methyl triflate under basic conditions (Scheme 9) [121,122]. Biodistribution studies with [ 18 F] 20 in mice revealed a high brain uptake (4%–5%ID/g) at 5 min post injection besides the highest accumulation of this radioligand in heart (10%–11%ID/g) [122]. In microPET imaging studies with [ 18 F] 20 and [ 11 C] 21 , both radioligands displayed rapid uptake and homogenous distribution in the mouse brain followed by a fast wash out [121,122].…”

Section: Pde7 Radioligandsmentioning

confidence: 99%

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Novel Radioligands for Cyclic Nucleotide Phosphodiesterase Imaging with Positron Emission Tomography: An Update on Developments Since 2012

et al. 2016

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Cyclic nucleotide phosphodiesterases (PDEs) are a class of intracellular enzymes that inactivate the secondary messenger molecules, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Thus, PDEs regulate the signaling cascades mediated by these cyclic nucleotides and affect fundamental intracellular processes. Pharmacological inhibition of PDE activity is a promising strategy for treatment of several diseases. However, the role of the different PDEs in related pathologies is not completely clarified yet. PDE-specific radioligands enable non-invasive visualization and quantification of these enzymes by positron emission tomography (PET) in vivo and provide an important translational tool for elucidation of the relationship between altered expression of PDEs and pathophysiological effects as well as (pre-)clinical evaluation of novel PDE inhibitors developed as therapeutics. Herein we present an overview of novel PDE radioligands for PET published since 2012.

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PET Imaging of Phosphodiesterases in Brain

Ooms

Bormans

2020

PET and SPECT of Neurobiological Systems

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Synthesis and preclinical evaluation of an 18 F labeled PDE7 inhibitor for PET neuroimaging

Cited by 12 publications

References 25 publications

Development of a New Radiofluorinated Quinoline Analog for PET Imaging of Phosphodiesterase 5 (PDE5) in Brain

Development of a New Radiofluorinated Quinoline Analog for PET Imaging of Phosphodiesterase 5 (PDE5) in Brain

Novel Radioligands for Cyclic Nucleotide Phosphodiesterase Imaging with Positron Emission Tomography: An Update on Developments Since 2012

PET Imaging of Phosphodiesterases in Brain

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