Abstract
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.
Highlights
The phosphodiesterases (PDEs) are a large family of enzymes that regulate the cellular levels of two important signalling molecules: the secondary messengers cyclic adenosine 31,51-monophosphate and cyclic guanosine 31,51-monophosphate
Phosphodiesterases (PDEs) are enzymes that play a major role in cell signalling by hydrolysing the secondary messengers cyclic adenosine monophosphate and/or cyclic guanosine monophosphate throughout the body and brain
To visualize and quantify the expression of this enzyme in brain, we developed a radiotracer for specific Positron emission tomography (PET) imaging of PDE5
Summary
The phosphodiesterases (PDEs) are a large family of enzymes that regulate the cellular levels of two important signalling molecules: the secondary messengers cyclic adenosine 31,51-monophosphate (cAMP) and cyclic guanosine 31,51-monophosphate (cGMP) This control results from their hydrolysing activity on the phosphodiester bonds of the free cyclic nucleotides. Chronic intraperitoneal injection of sildenafil downregulated the proapoptotic proteins caspase-3 and B-cell lymphoma 2-associated X and increased antiapoptotic molecules such as B-cell lymphoma protein-2 and brain-derived neurotrophic factor in aged mice [19] All these findings highlight the need to improve the tools available to reassess both the in vivo effects of the different cGMP-PDE5 inhibitors and their role in pathological conditions. Even if there are plenty specific and high affinity inhibitors of PDE5 already published, only a few radiotracers have been evaluated for PET imaging of this enzyme until now (Figure 1) [20,21,22]. AoffteNr A60DmPHin.inAcfutebrat6io0nmofin[18iFn]cIuCbFa2t4io0n27,onf o[1i8nFt]aIcCtFtr2a4c0e2r7a,nndoa isnlitgahcttlytrdacifefrereanntdraadisoli-gMhLtlCy adnifdfe-rHenPtLrCadpiroo-fiMleLCwaasnodb-sHerPvLeCd cpormofpilaerwedastootbhseerinvevdivcoodmaptaa.rMedatinoltyhae sininvgilveopdoaltaar.rMadaiionmlyeatasbionlgitlee apcocloaur nrtaidngiom93e%tabooflitthee atcoctoaul natcitnivgit9y3w%asofdtehteectteodta(ldaacttaivnitoyt swhaoswdne).tecAtesdob(dseartvaednoatlssohofowrno).thAers roabdsieortvreadcearslsionfvoerstoitghaetredraidniooturracgerrosuipn,vtehsetimgaetteadboinlisomurmgaroyubpe, ftahsetemr eintavbiotrlois, mdempeanydbinegfaosntetrhienavsistraoy, cdoenpdeintdioinnsg aonnd tthheeraesfosarey pcroonbdaibtiloynrsesaunldtintgheinreafo1r8eF-pcroonbtaabinlyinrgepsuroltdinugctionriagi1n8Fa-tcinongtfarionmingmeptraobdoulicct ionrtiegrimnaetdiniagtefsraofmtermfuerttahbeorloicxiidnatteiromn epdroiacteessseasf.teInrvfeusrtitghaetrioonxoidf athtieonnopnr-roacdeisosaecst.ivInevceosmtipgoautinodn inofvitthroe dneomn-orandstiroaatcetdivtehreceommpajoournmdetianbovliitteros indethmeoUnsVt-rHatPeLdCtchhrreoemmataojgorramm. eOtanbeooliftethsemin, wthiteh aUrVet-eHnPtiLoCn tcihmroemofa2to9gmraimn,.cOounledobfethidemen,twifiietdh aasrethteenatlicoonhtoiml 1e. of 29 min, could be identified as the alcohol 1
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