New potent A₁ adenosine 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 A₁ adenosine 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 A₁ receptor 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.