000825290 001__ 825290
000825290 005__ 20210129225254.0
000825290 037__ $$aFZJ-2016-07754
000825290 041__ $$aEnglish
000825290 1001_ $$0P:(DE-Juel1)144437$$aKreft, Sabrina$$b0$$eCorresponding author
000825290 1112_ $$a21st International Symposium on Radiopharmaceutical Sciences$$cColumbia$$d2015-05-26 - 2015-05-31$$gISRS 2015$$wUSA
000825290 245__ $$aNew metabolically enhanced PET radioligands for the adenosine A(1) receptor
000825290 260__ $$c2015
000825290 3367_ $$033$$2EndNote$$aConference Paper
000825290 3367_ $$2DataCite$$aOther
000825290 3367_ $$2BibTeX$$aINPROCEEDINGS
000825290 3367_ $$2DRIVER$$aconferenceObject
000825290 3367_ $$2ORCID$$aLECTURE_SPEECH
000825290 3367_ $$0PUB:(DE-HGF)6$$2PUB:(DE-HGF)$$aConference Presentation$$bconf$$mconf$$s1482390058_973$$xPlenary/Keynote
000825290 520__ $$aObjectives 8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX) is an established receptor ligand to examine cerebral adenosine A1 receptors in humans by positron-emission-tomography (PET) [1]. A large drawback of this compound is its short biological half-life of about only ten minutes in human blood plasma [2]. Therefore alternative, slower metabolizing 18F-labelled adenosine A1 receptor ligands for in vivo imaging were developed, while maintaining a high affinity. Methods The binding affinity of various xanthine derivatives to the adenosine A1 receptor was examined. Based on these studies as well as the results of in-house studies on metabolites, the xanthine derivatives 8-cyclobutyl-1-cyclopropymethyl-3-(3-fluoropropyl)xanthine (1) and 1-cyclopropylmethyl-3-(3-fluoropropyl)-8-(1-methylcyclobutyl)xanthine (2) were designed as alternatives of CPFPX. After synthesis of these compounds, their affinity to the adenosine A1 receptor was investigated by competitive assays. The mesylate derivatives were synthesized as precursors for nucleophilic 18F-labelling and the radiofluorinated ligands were used for autoradiographic studies. Furthermore, the metabolism of 1 and 2 was examined in vitro using human liver microsomes. Results The new xanthine derivatives were synthesized in 13 steps with total yields of 1.8 % (1) and 1.5 % (2). In binding studies both compounds showed nanomolar affinities to the adenosine A1 receptor. [18F]CBCPM was obtained by radiofluorination with a radiochemical yield of 21.3 ± 3.8 % and a molar activity of 12.3 ± 0.2 GBq/µmol. In case of [18F]CPMMCB, a radiochemical yield of 14.4 ± 2.5 % and a molar activity of 36.5 ± 1.1 GBq/µmol could be achieved. In vitro autoradiography with brain slices of rat showed for both compounds the expected enrichment in regions known to have a high adenosine A1 receptor expression, while exhibiting the necessary low unspecific binding. Further studies proved a significantly slower metabolism in vitro of both new xanthine derivatives than CPFPX. Conclusions Two new radiofluorinated affine and specific xanthine derivatives were developed as possible radioligands for the adenosine A1 receptor with a distinct higher stability than CPFPX. Acknowledgements  References [1] Holschbach M. H. et al. (2002) J. Med. Chem., 45, 5150-5156. [2] Bier D. et al. (2006) Drug Metab. Dispos., 34, 570-576.
000825290 536__ $$0G:(DE-HGF)POF3-573$$a573 - Neuroimaging (POF3-573)$$cPOF3-573$$fPOF III$$x0
000825290 7001_ $$0P:(DE-Juel1)131810$$aBier, Dirk$$b1$$ufzj
000825290 7001_ $$0P:(DE-Juel1)131824$$aHolschbach, Marcus$$b2$$ufzj
000825290 7001_ $$0P:(DE-Juel1)131847$$aSchulze, Annette$$b3$$ufzj
000825290 7001_ $$0P:(DE-Juel1)131816$$aCoenen, Heinrich Hubert$$b4$$ufzj
000825290 909CO $$ooai:juser.fz-juelich.de:825290$$pVDB
000825290 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)131810$$aForschungszentrum Jülich$$b1$$kFZJ
000825290 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)131824$$aForschungszentrum Jülich$$b2$$kFZJ
000825290 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)131847$$aForschungszentrum Jülich$$b3$$kFZJ
000825290 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)131816$$aForschungszentrum Jülich$$b4$$kFZJ
000825290 9131_ $$0G:(DE-HGF)POF3-573$$1G:(DE-HGF)POF3-570$$2G:(DE-HGF)POF3-500$$3G:(DE-HGF)POF3$$4G:(DE-HGF)POF$$aDE-HGF$$bKey Technologies$$lDecoding the Human Brain$$vNeuroimaging$$x0
000825290 9141_ $$y2016
000825290 915__ $$0StatID:(DE-HGF)0550$$2StatID$$aNo Authors Fulltext
000825290 920__ $$lyes
000825290 9201_ $$0I:(DE-Juel1)INM-5-20090406$$kINM-5$$lNuklearchemie$$x0
000825290 980__ $$aconf
000825290 980__ $$aVDB
000825290 980__ $$aUNRESTRICTED
000825290 980__ $$aI:(DE-Juel1)INM-5-20090406