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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.

ejnmmi research

Synthesis and evaluation in rats of homologous series of [18F]-labeled dopamine D2/3 receptor agonists based on the 2-aminomethylchroman scaffold as potential PET tracers