Breidenbach, M. (Corresponding author)FZJ*

2004
Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag Jülich

Report No.: Juel-4132

Abstract: Alteration in the density of CNS adenosine receptors (ARs) is thought to contribute to some neurodegenerative disorders like Parkinsons disease. This creates a demand for PET-tracers, suitable for measurement of the density of A$_{2A}$ARs in human brain in vivo. Therefore A$_{2A}$AR selective and high affine ligands, n.c.a. labelled with positron emitting nuclides, are needed that bind specifically in vivo to the receptor and thus could be used for the imaging of A$_{2A}$AR-rich brain regions. Because of radiochemical reasons or their low water solubility, high lipophilicity and tendency for unspecific binding, none of the known A$_{2A}$-selective and high affine ligands is suitable for in vivo brain imaging with PET. The aim of this work was to synthesize and evaluate new potential PET-tracers based on one of the lead-structures of known A$_{2A}$AR antagonists, the 6-aminopurine. A series of N$^{2}$, C8 and N9 differentialy substituted 2,6-diaminopurines has been synthesized following two synthetic pathways that have been developed. For evaluation of the substances their affinities towards the high-affinity AR subtypes A$_{1}$ and A$_{2A}$ were specified in in vitro competition experiments using pig brain membrane preparations. In addition, their water solubility was determined by a HPLC/UV-method and their logP-values calculated. Structure-activity-relationships were analyzed revealing that N$^{2}$ hydroxy- phenylethyl and C8 2-furyl substituted 2,6-diaminopurines exhibit affinities of about 20 nM and selectivities up to 1000-fold towards A$_{2A}$AR if N9 is alkylated. By N9 fluorethylation or methylation as well as electrophilic iodination of the N$^{2}$ hydroxy-phenylethyl substituent it is possible to obtain ligands with suitable affinity and selectivity that potentially lend themselves for in vivo applications. No-carrier-added labelling of these substances with either fluorine-18, carbon-11 or iodine-131 (used as a substitute for iodine-120,124) was optimized and radiochromatographic conditions for isolation were elaborated. N.c.a. radiolabelling with [$^{18}$F]fluoride and electrophilic iodine- 131 was performed with good radiochemical yields of about 70 %, methylation with [$^{11}$C]methyliodide supplied about 60 %. Evaluation of the radioligands by in vitro autoradiography with rat brain slices was performed to measure unspecific binding and uptake in target tissue, but neither radioligand showed the expected selective binding to the A$_{2A}$AR rich striatal region.

Keyword(s): PET (positron emission tomography) ; neuroscience ; CNS (central nervous system)

1. Nuklearchemie (INB-4)