Synthesis and Evaluation in Rats of the Dopamine D-2/3 Receptor Agonist F-18-AMC20 as a Potential Radioligand for PET

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

4 Citations (Scopus)


Dopamine D-2/3 receptor (D2/3R) agonist PET tracers are better suited for the imaging of synaptic dopaminergic neurotransmission than D2/3R antagonists and may also offer the opportunity to study in vivo the high-affinity state of D2/3R (D(2/3)RHigh). With the aim to develop F-18-labeled D2/3R agonists suitable for widespread clinical application, we report here on the synthesis and in vitro and in vivo evaluation of a D2/3R agonist ligand from the aminomethyl chromane (AMC) class-(R)-2-[(4-F-18-fluorobenzylamino) methyl] chroman-7-ol (F-18-AMC20). Methods: In vitro affinities of AMC20 toward dopaminergic receptor subtypes were measured in membrane homogenates prepared from HEK293 cells expressing human dopamine receptors. Agonism of AMC20 was assessed in the arrestin recruitment assay in Chinese hamster ovary-K-1 cells expressing the long isoform of D2R (D(2)RLong). D2/3R-specific binding of F-18-AMC20 was evaluated in brain slices of Sprague-Dawley rats by in vitro autoradiography and in living rats by in vivo small-animal PET imaging and ex vivo autoradiography. PET data were analyzed with 1-and 2-tissue compartmental models, the simplified reference tissue model, and Logan graphical analysis. Specificity of binding was tested by blocking D2/3R with raclopride (coincubation with 10 mu M in vitro, administration of 1.0 mg/kg in vivo). Results: In membrane homogenates, AMC20 demonstrated picomolar affinity at D(2)RHigh (mean inhibition constant [K-i] = 85 pM) and excellent selectivity against the low-affinity state of D2R (D(2)RLow) (mean K-i = 84 nM, 988-fold selectivity) and D-1-like receptors (mean Ki 5 5,062 nM at D1R). The efficacy of AMC20 was 90% of that of dopamine in the arrestin recruitment assay. Up to 70% of total binding of F-18-AMC20 in the D2/3R-rich striatum in rat brain slices was D2/3R-specific; in living rats, the uptake ratio between the striatum and the D2/3R-poor cerebellum reached 2.0-2.5, depending on the measurement method. Radiometabolites of F-18-AMC20 did not enter the brain. Striatal binding potential of F-18-AMC20 varied between 0.49 and 0.59 depending on the estimation method. Pretreatment with 1 mg of raclopride per kilogram reduced the apparent specific binding of F-18-AMC20 in the striatum. Conclusion: F-18-AMC20 shows specific binding to D2/3R in the striatum of living rats. Further optimization of the chemical structure of F-18-AMC20 can lead to F-18-labeled D-2/3 agonist PET tracers more suitable for in vivo clinical application.

Original languageEnglish
Pages (from-to)133-139
Number of pages7
JournalJournal of Nuclear Medicine
Issue number1
Publication statusPublished - Jan-2015


  • agonist tracer
  • dopamine receptor
  • PET
  • F-18

Cite this