guest ::
| Home > Publications database > Synthesis and in vitro evaluation of radiobrominated adenosine A(1) receptor ligand [*Br] CPBPX |
| Home > Publications database > Synthesis and in vitro evaluation of radiobrominated adenosine A(1) receptor ligand [*Br] CPBPX |
| Conference Presentation (Plenary/Keynote) | FZJ-2016-07759 |
; ; ; ;
2015
Abstract: Objectives [18F]CPFPX (8-cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine) [1] is an established ligand for investigation of the adenosine A1 receptor (A1AR) in man using PET. The iodinated derivative [131I]CPIPX (8-cyclopentyl-3-[(E)-3-[131I]iodoprop-2-en-1-yl]-1-propylxanthine) [2] has been synthesized as well and evaluated with regard to its binding profile. Since no radiobrominated A1AR ligand is known so far, the synthesis of the radiobrominated analogue [*Br]CPBPX (8-cyclopentyl-3-[(E)-3-[*Br]bromoprop-2-en-1-yl]-1-propylxanthine) was performed for closing the gap of lipophilicity in this xanthine series, which is important for systematic studies. Methods The applied radionuclide mixture of 76,77,82Br (*Br) was produced via natSe(p,xn)-reactions on the new target material NiSe at the BC1710 cyclotron of the Forschungszentrum Jülich and isolated as sodium [*Br]bromide in no-carrier-added form [3]. The radiosynthesis of [*Br]CPBPX was carried out via radiobromo-destannylation of the tributyltin precursor by in situ oxidation of n.c.a. [*Br]bromide. The binding profile of the new ligand to the A1AR was investigated in vitro. For the determination of the logP value of [*Br]CPBPX, a new experimental procedure had to be developed, as the radioligand decomposes in water/octanol yielding a polar compound (probably free bromide). The conventional liquid-liquid extraction was followed by an additional thin layer chromatography of both phases, in order to separate hydrophilic from lipophilic components, and hence to allow the determination of the “true” logP value. Results [*Br]CPBPX was obtained after 0.5 min at RT in radiochemical yields of 54 ± 8 % with a molar activity of 8.6 GBq/µmol. The latter would be enhanced by using enriched selenium as target material. In competition studies a KI-value of 26 nM was determined for CPBPX (KI of CPFPX in relation to [3H]DPCPX 4.9 nM). Preliminary in vitro autoradiographic studies on rat brain slices show an increased accumulation of [*Br]CPBPX in areas with high A1AR density and a fraction of specific binding of ca. 20 %. Using the improved experimental procedure, a logP value of 3.4 was determined for [*Br]CPBPX. Conclusions [*Br]CPBPX closes the gap of lipophilicity of the known fluoro and iodo derivatives, but its affinity to the A1AR is more similar to the iodine analogue. With regard to the determination of experimental logP values of radiohaloalkylated ligands, the necessity of an improved procedure was revealed, as such components may release halide, falsifying the experimental results. Acknowledgements References [1] Holschbach M. H. et al. (2002) J. Med. Chem., 45, 5150-5156. [2] Sihver W. et al. (2003) Nucl. Med. Biol., 30, 661-668. [3] Breunig K. et al. Radiochim. Acta (in press).
|
The record appears in these collections: |