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

Shalgunov, Vladimir; Wieringen, Jan Peter Van; Janssen, Henk M.; Fransen, Peter; Dierckx, Rudi; Michel, Martin C.; Booij, Jan; Elsinga, Philip H.

doi:10.2967/jnumed.114.145466

Cited by 6 publications

(5 citation statements)

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“…A striatum-to-cerebellum ratio of 2.08 is on par with the value of 2 reported in rats for [ 18 F]5-OH-FPPAT [ 20 ] and with the value of 1.97 obtained for our other separately evaluated AMC derivative [ 18 F]AMC20 [ 34 ]. However, the striatal BP ND values of 0.51–0.63 obtained for [ 18 F]FEt-AMC13 are lower than the values of at least 0.8–1.0 reported in rodents for existing [ 11 C]-labeled D 2/3 agonists [ 19 , 29 , 31 ].…”

Section: Discussionsupporting

confidence: 78%

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

et al. 2015

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BackgroundAgonist positron emission tomography (PET) tracers for dopamine D2/3 receptors (D2/3Rs) 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 [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.MethodsThe 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.ResultsHomologues 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 ([18F]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 [18F]FEt-AMC13 did not enter the brain. In vitro, application of 10 μmol/L raclopride reduced D2/3R-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 D2/3R-specific binding in the striatum.ConclusionsVarying 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 D2/3R imaging by PET.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-015-0119-x) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 78%

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

et al. 2015

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“…Apomorphine analogs, 11 C-NPA in PET studies of nonhuman primates clearly showed binding to the caudate-putamen, similar to that found for 11 C-raclopride (Finnema et al, 2009; Hwang et al, 2005). More recently, agonists 18 F-MCL-524, apomorphine analogs (Finnema et al, 2014; Sromek et al, 2014) and 18 F-aminomethylchroman analogs (Shalgunov et al, 2015a,b) have been reported for imaging dopamine D2 and D3 receptors. 11 C-PHNO is a modified aminotetralin derivative and has high-affinity for D2 and D3 receptor subtypes thus suggesting that PHNO binds to D2-high affinity state (HA) and D3 receptors.…”

Section: | Introductionmentioning

confidence: 99%

PET radiotracer development for imaging high‐affinity state of dopamine D2 and D3 receptors: Binding studies of fluorine‐18 labeled aminotetralins in rodents

Majji

Kaur

Constantinescu

et al. 2016

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Imaging the high-affinity, functional state (HA) of dopamine D2 and D3 receptors has been pursued in PET imaging studies of various brain functions. We report further evaluation of 18F-5-OH-FPPAT, and the newer 18F-5-OH-FHXPAT and 18F-7-OH-FHXPAT. Syntheses of 18F-5-OH-FHXPAT and 18F-7-OH-FHXPAT were improved by modifications of our previously reported procedures. Brain slices and brain homogenates from male Sprague-Dawley rats were used with the 3 radiotracers (74–111 kBq/cc). Competition with dopamine (1–100 nM) and Gpp(NH)p (10–50 μM) were carried out to demonstrate binding to dopamine D2 and D3 HA-states and binding kinetics of 18F-5-OH-FPPAT measured. Ex vivo brain slice autoradiography was carried out on rats administered with 18F-5-OH-FHXPAT to ascertain HA-state binding. PET/CT imaging in rats and wild type (WT) and D2 knock-out mice were carried out using 18F-7-OH-FHXPAT (2–37 MBq). Striatum was clearly visualized by the three radiotracers in brain slices and dopamine displaced more than 80% of binding, with dissociation rate in homogenates of 2.2 × 10−2 min−1 for 18F-5-OH-FPPAT. Treatment with Gpp(NH)p significantly reduced 50–80% striatal binding with faster dissociation rates (5.0 × 10−2 min−1), suggesting HA-state binding of 18F-5-OH-FPPAT and 18F-5-OH-FHXPAT. Striatal binding of 18F-5-OH-FHXPAT in ex vivo brain slices were sensitive to Gpp(NH)p, suggesting HA-state binding in vivo. PET binding ratios of 18F-7-OH-FHXPAT in rat brain were ventral striatum/cerebellum=2.09 and dorsal striatum/cerebellum=1.65; similar binding ratios were found in the D2 WT mice. These results suggest that in vivo PET measures of agonists in the brain at least in part reflect binding to the membrane-bound HA-state of the dopamine receptor.

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“…Also, we cannot exclude the fact that radiolabelled metabolites were formed that have passed the blood-brain barrier. However, for a similar compound (AMC20), we found that 95% of the radioactivity from a brain tissue extract (35 min after injection) was intact 18 F-AMC20 and that radiometabolites of 18 F-AMC20 were hydrophilic and did not pass the blood-brain barrier [ 34 ]. Since our present compound has a similar structure, we believe that it is unlikely that formation of radiometabolites will have significantly influenced the results.…”

Section: Discussionmentioning

confidence: 99%

Ex Vivo Characterization of a Novel Iodine-123-Labelled Aminomethylchroman as a Potential Agonist Ligand for SPECT Imaging of Dopamine D_2/3Receptors

Wieringen

Bruin

Janssen

et al. 2014

International Journal of Molecular Imaging

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For imaging of dopamine D2/3 receptors, agonist tracers are favoured over antagonists because they are more sensitive to detection of dopamine release and because they may selectively label the high-affinity receptor state. We have developed novel D2/3 receptor selective agonists that can be radiolabelled with [123I], which label is advantageous over most other labels, such as carbon-11, as it has a longer half-life. Particularly, we considered (R) N-[7-hydroxychroman-2-yl]-methyl 4-iodobenzyl amine (compound 1) as an attractive candidate for development as it shows high binding affinity to D2/3 receptors in vitro, and here we report on the characterization of this first [123I]-labelled D2/3 receptor agonist radiopharmaceutical intended for SPECT imaging. The appropriate tin precursor for [123I]-1 was developed and was successfully radiolabelled with iodine-123 giving a moderate yield (30–35%) and a good purity (>95%) for [123I]-1. In biodistribution experiments in Wistar rats intravenous injection of [123I]-1 resulted in a fast brain uptake, where the observed binding in the D2/3 receptor-rich striatum was slightly higher than that in the cerebellum 30 min to 4 h p.i. Storage phosphor imaging experiments, however, did not show specific D2/3 receptor binding. In conclusion, despite promising in vitro data for 1, neither specific ex vivo binding nor high signal-to-noise ratios were found in rodents for [123I]-1.

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Synthesis and Evaluation in Rats of the Dopamine D_2/3Receptor Agonist¹⁸F-AMC20 as a Potential Radioligand for PET

Cited by 6 publications

References 22 publications

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

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

PET radiotracer development for imaging high‐affinity state of dopamine D2 and D3 receptors: Binding studies of fluorine‐18 labeled aminotetralins in rodents

Ex Vivo Characterization of a Novel Iodine-123-Labelled Aminomethylchroman as a Potential Agonist Ligand for SPECT Imaging of Dopamine D_2/3Receptors

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Synthesis and Evaluation in Rats of the Dopamine D2/3Receptor Agonist18F-AMC20 as a Potential Radioligand for PET

Cited by 6 publications

References 22 publications

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

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

PET radiotracer development for imaging high‐affinity state of dopamine D2 and D3 receptors: Binding studies of fluorine‐18 labeled aminotetralins in rodents

Ex Vivo Characterization of a Novel Iodine-123-Labelled Aminomethylchroman as a Potential Agonist Ligand for SPECT Imaging of Dopamine D2/3Receptors

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Synthesis and Evaluation in Rats of the Dopamine D_2/3Receptor Agonist¹⁸F-AMC20 as a Potential Radioligand for PET

Ex Vivo Characterization of a Novel Iodine-123-Labelled Aminomethylchroman as a Potential Agonist Ligand for SPECT Imaging of Dopamine D_2/3Receptors