This title appears in the Scientific Report :
2015
Please use the identifier:
http://hdl.handle.net/2128/8573 in citations.
Untersuchung von Struktur-Eigenschaftsbeziehungen von Adenosin A$_{1}$-Rezeptorliganden zur Entwicklung$^{18}$F-markierter Radioliganden
Untersuchung von Struktur-Eigenschaftsbeziehungen von Adenosin A$_{1}$-Rezeptorliganden zur Entwicklung$^{18}$F-markierter Radioliganden
For the development of new analogues of the highly affine and selective radioligand 8-cyclopentyl-3-(3-[$^{18}$F]fluoropropyl)-1-propylxanthine ([$^{18}$F]CPFPX) for the adenosine A$_{1}$ receptorwith improved metabolic stability for molecular imaging by positron-emission-tomography theaffinities of...
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Personal Name(s): | Kreft, Sabrina (Corresponding Author) |
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Contributing Institute: |
Nuklearchemie; INM-5 |
Published in: | 2015 |
Imprint: |
Jülich
Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag
2015
|
Physical Description: |
160 pp |
Document Type: |
Report Book |
Research Program: |
ohne Topic |
Series Title: |
Berichte des Forschungszentrums Jülich
4383 |
Link: |
OpenAccess OpenAccess |
Publikationsportal JuSER |
For the development of new analogues of the highly affine and selective radioligand 8-cyclopentyl-3-(3-[$^{18}$F]fluoropropyl)-1-propylxanthine ([$^{18}$F]CPFPX) for the adenosine A$_{1}$ receptorwith improved metabolic stability for molecular imaging by positron-emission-tomography theaffinities of different in-house synthesized xanthine derivatives to the adenosine A$_{1}$ receptorwere investigated, in order to reveal relationships between molecular structure and bindingproperties of these ligands. Based on these studies, on the results of earlier studies on metabolism in-house, known biological properties as well as computed lipophilicity parameters of various xanthinederivatives, new compounds were designed as possible adenosine A$_{1}$ receptor ligands. Froma series of xanthine derivatives 8-cyclobutyl-1-cyclopropylmethyl-3-(3-fluoropropyl)xanthine(CBCPM) and 1-cyclopropylmethyl-3-(3-fluoropropyl)-8-(1-methylcyclobutyl)xanthine(CPMMCB) emerged as the most suitable candidates. The non-radioactive target compounds and corresponding mesylate precursors for radiofluorination could successfully be synthesized. The labelled products were obtained by nucleophilic substitution with no-carrier-added [$^{18}$F]fluoride and subsequent deprotection. [$^{18}$F]CBCPM was obtained and isolated in radiochemical yields of 21,3 ± 3,8 % and a molar activity of 12.3 ± 0.2 GBq/$\mu$mol (0.33 ± 0.01 Ci/$\mu$mol). In the case of [$^{18}$F]CPMMCB, a radiochemical yield of 14.4 ± 2.5 % and a molar activity of 36.5 ± 1.1 GBq/$\mu$mol(0.99 ± 0.03 Ci/$\mu$mol) could be achieved. $\textit{In vitro}$ competition assays revealed a high affinity to the adenosine A$_{1}$ receptor for both compounds. The inhibition constants were K$_{l}$ = 10.1 nM (CBCMP) and K$_{l}$ = 15.5 nM (CPMMCB), while the K$_{l}$ value of the established CPFPX as reference compound in this test series was 15.1 nM. Autoradiographic studies confirmed the high affinity as well as high selectivity of the radiofluorinated compounds to the target receptor. The specific binding amounted to 86.8 % for [$^{18}$F]CBCPM and 84.8 % for [$^{18}$F]CPMMCB. In $\textit{in vitro}$ studies usinghuman liver microsomes both new non labeled xanthine derivatives show a distinctly slowermetabolism than CPFPX. Thus, it was successful to develop [$^{18}$F]CBMCP and [$^{18}$F]CPMMCB as two new, highly affine and selective xanthine derivatives, potential radioligands for the adenosine A$_{1}$ receptor. The slower degradation of the ligands in $\textit{in vitro}$ studies supports reasonable presumptions of asignificantly higher $\textit{in vivo}$ stability causing the aspired longer biological half-life. |