Synthesis and evaluation in rats of homologous series of [(18)F]-labeled dopamine D(2/3) receptor agonists based on the 2-aminomethylchroman scaffold as potential PET tracers

BACKGROUND: Agonist positron emission tomography (PET) tracers for dopamine D(2/3) receptors (D(2/3)Rs) offer greater sensitivity to changes in endogenous dopamine levels than D(2/3)R antagonist tracers. D(2/3)R agonist tracers currently available for clinical research are labeled with the short-lived isotope carbon-11, which limits their use. We aimed to develop high-affinity D(2)R agonists amenable for labeling with the longer-living fluorine-18. Here, we report the evaluation as potential PET tracers of two homologous series of [(18)F]fluorinated tracers based on the 2-aminomethylchroman-7-ol (AMC) scaffold: (R)-2-((4-(2-fluoroalkoxy)benzylamino)methyl)chroman-7-ols (AMC13 homologues) and (R)-2-((2-(4-(4-(fluoroalkoxy)phenyl)piperazin-1-yl)ethylamino)methyl)chroman-7-ols (AMC15 homologues). We varied the length of the (18)F-fluoroalkyl chain in these structures to balance brain penetration and non-specific binding of the radioligands by adjusting their lipophilicity. METHODS: The tracers were evaluated in brain slices of Sprague-Dawley rats by in vitro autoradiography and in living rats by microPET imaging and ex vivo autoradiography. PET data were analyzed with one- and two-tissue compartmental models (1TCM/2TCM), simplified reference tissue model (SRTM), and Logan graphical analysis. Specificity of binding was tested by blocking D(2/3)R with raclopride. RESULTS: Homologues with a shorter fluoroalkyl chain consistently showed greater D(2/3)R-specific-to-total binding ratios in the striatum than those with longer chains. The fluoroethoxy homologue of AMC13 ([(18)F]FEt-AMC13) demonstrated the highest degree of D(2/3)R-specific binding among the evaluated tracers: mean striatum-to-cerebellum uptake ratio reached 4.4 in vitro and 2.1/2.8 in vivo/ex vivo (PET/autoradiography). Striatal binding potential (BP(ND)) relative to cerebellum was 0.51–0.63 depending on the estimation method. Radiometabolites of [(18)F]FEt-AMC13 did not enter the brain. In vitro, application of 10 μmol/L raclopride reduced D(2/3)R-specific binding of [(18)F]FEt-AMC13 in the striatum by 81 %. In vivo, pre-treatment with 1 mg/kg (2.9 μmol/kg) raclopride led to 17–39 % decrease in D(2/3)R-specific binding in the striatum. CONCLUSIONS: Varying the length of the [(18)F]fluoroalkyl chain helped improve the characteristics of the original candidate tracers. Further modifications of the current lead [(18)F]FEt-AMC13 can provide an agonist radiopharmaceutical suitable for D(2/3)R imaging by PET. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13550-015-0119-x) contains supplementary material, which is available to authorized users.