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

Vladimir Shalgunov, Jan-Peter van Wieringen, Henk M. Janssen, P. Michel Fransen, Rudi A. J. O. Dierckx, Martin C. Michel, Jan Booij, Philip H. Elsinga*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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 D2/3R antagonist tracers. D2/3R 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 D2R agonists amenable for labeling with the longer-living fluorine-18. Here, we report the evaluation as potential PET tracers of two homologous series of [F-18]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 F-18-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 D2/3R with raclopride.

Results: Homologues with a shorter fluoroalkyl chain consistently showed greater D2/3R-specific-to-total binding ratios in the striatum than those with longer chains. The fluoroethoxy homologue of AMC13 ([F-18]FEt-AMC13) demonstrated the highest degree of D2/3R-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 (BPND) relative to cerebellum was 0.51-0.63 depending on the estimation method. Radiometabolites of [F-18]FEt-AMC13 did not enter the brain. In vitro, application of 10 mu mol/L raclopride reduced D2/3R-specific binding of [F-18]FEt-AMC13 in the striatum by 81 %. In vivo, pre-treatment with 1 mg/kg (2.9 mu mol/kg) raclopride led to 17-39 % decrease in D2/3R-specific binding in the striatum.

Conclusions: Varying the length of the [F-18]fluoroalkyl chain helped improve the characteristics of the original candidate tracers. Further modifications of the current lead [F-18]FEt-AMC13 can provide an agonist radiopharmaceutical suitable for D2/3R imaging by PET.

Original languageEnglish
Article number41
Number of pages13
JournalEJNMMI Research
Volume5
DOIs
Publication statusPublished - 25-Jul-2015

Keywords

  • Agonist tracer
  • Dopamine receptor
  • PET
  • Fluorine-18
  • POSITRON-EMISSION-TOMOGRAPHY
  • HIGH-AFFINITY STATE
  • IN-VIVO
  • ENDOGENOUS DOPAMINE
  • ANTERIOR-PITUITARY
  • DRUG-ABUSE
  • BINDING
  • RADIOTRACER
  • ANTAGONIST
  • BRAIN

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