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Open Access 01-12-2015 | Original research

Synthesis and evaluation in rats of homologous series of [¹⁸F]-labeled dopamine D_2/3 receptor agonists based on the 2-aminomethylchroman scaffold as potential PET tracers

Authors: 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

Published in: EJNMMI Research | Issue 1/2015

Abstract

Background

Agonist positron emission tomography (PET) tracers for dopamine D_2/3 receptors (D_2/3Rs) offer greater sensitivity to changes in endogenous dopamine levels than D_2/3R antagonist tracers. D_2/3R 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 [¹⁸F]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 ¹⁸F-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_2/3R with raclopride.

Results

Homologues with a shorter fluoroalkyl chain consistently showed greater D_2/3R-specific-to-total binding ratios in the striatum than those with longer chains. The fluoroethoxy homologue of AMC13 ([¹⁸F]FEt-AMC13) demonstrated the highest degree of D_2/3R-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 (BP_ND) relative to cerebellum was 0.51–0.63 depending on the estimation method. Radiometabolites of [¹⁸F]FEt-AMC13 did not enter the brain. In vitro, application of 10 μmol/L raclopride reduced D_2/3R-specific binding of [¹⁸F]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_2/3R-specific binding in the striatum.

Conclusions

Varying the length of the [¹⁸F]fluoroalkyl chain helped improve the characteristics of the original candidate tracers. Further modifications of the current lead [¹⁸F]FEt-AMC13 can provide an agonist radiopharmaceutical suitable for D_2/3R imaging by PET.

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Title: 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
Authors: 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
Publication date: 01-12-2015
Publisher: Springer Berlin Heidelberg
Published in: EJNMMI Research / Issue 1/2015
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/s13550-015-0119-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Synthesis and evaluation in rats of homologous series of [¹⁸F]-labeled dopamine D_2/3 receptor agonists based on the 2-aminomethylchroman scaffold as potential PET tracers

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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