New potent A1adenosine receptor radioligands for positron emission tomography.
8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX) is meanwhile an accepted receptor ligand to examine the A1adenosine receptor (A1AR) in humans by positron emission tomography (PET). A major drawback of this compound is its rather fast metabolic degradation in vivo. Therefore two new xanthine derivatives, namely 8-cyclobutyl-1-cyclopropymethyl-3-(3-fluoropropyl)xanthine (CBCPM; 5) and 1-cyclopropylmethyl-3-(3-fluoropropyl)-8-(1-methylcyclobutyl)xanthine (CPMMCB; 6) were designed and synthesized as potential alternatives to CPFPX. In membrane binding studies both compounds showed nanomolar affinity for the A1AR. In vitro autoradiographic studies of [18F]5 and [18F]6, using rat brain slices, showed the expected accumulation in regions known to have a high adenosine A1receptor expression while exhibiting the necessary low unspecific binding. However, in vitro metabolite studies using human liver microsomes revealed a comparable metabolic degradation rate for both new xanthine derivatives and CPFPX.
Institute of Neuroscience and Medicine - Nuclear chemistry, INM-5, Forschungszentrum Jülich, D-52425, Jülich, Germany.
Sabrina
S
Kreft
Institute of Neuroscience and Medicine - Nuclear chemistry, INM-5, Forschungszentrum Jülich, D-52425, Jülich, Germany. Electronic address: d.bier@fz-juelich.de.
Dirk
D
Bier
Institute of Neuroscience and Medicine - Nuclear chemistry, INM-5, Forschungszentrum Jülich, D-52425, Jülich, Germany.
Marcus H
MH
Holschbach
Institute of Neuroscience and Medicine - Nuclear chemistry, INM-5, Forschungszentrum Jülich, D-52425, Jülich, Germany.
Annette
A
Schulze
Institute of Neuroscience and Medicine - Nuclear chemistry, INM-5, Forschungszentrum Jülich, D-52425, Jülich, Germany.
Heinz H
HH
Coenen
D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002460:Cell Line; D004355:Drug Stability; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D014970:Xanthines / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics
D008024:Ligands; D043682:Receptor, Adenosine A1; D014970:Xanthines
A(1) adenosine receptor; Fluorine-18; Positron emission tomography; Radioligand; Xanthine; [(18)F]CPFPX