Synthesis and initial PET imaging of new potential dopamine D3 receptor radioligands (E)-4,3,2-[11C]methoxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides
Graphical abstract
Reported in this article are the synthesis and initial PET imaging of new potential dopamine D3 receptor radioligands (E)-4,3,2-[11C]methoxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides.
Introduction
The neurotransmitter dopamine is implicated in a number of physiological and pathophysiological processes, which regulate brain functions like motion, emotion, and cognition.1 Five subtypes of brain dopamine receptors have been classified into two major classes: the D1-like receptors including D1 and D5 receptors and D2-like receptors including D2, D3, and D4 receptors. The dopamine D2-like receptor subtypes, D2 and D3 receptors, are recognized as potential therapeutic targets for the treatment of various neurological and psychiatric disorders such as Parkinson’s disease, Huntington’s disease, and schizophrenia.2 An in vivo biomedical imaging technique, positron emission tomography (PET), coupled with appropriate receptor radioligands, has become a clinically valuable and accepted diagnostic tool to image brain diseases.3 The dopamine D2-like receptor was the first neuroreceptor to be visualized by PET with the tracer 3-N-[11C]methyl-spiperone ([11C]NMSP).4 There is a growing interest in developing positron-labeled D2 and D3 receptor antagonists as in vivo markers for use in PET, and many attempts have been made in this area.5, 6, 7 However, so far only [11C]raclopride has been extensively used in human clinical PET studies, because of its high affinity and great specificity for binding to cerebral dopaminergic D2 receptors.8 We have developed an improved synthetic approach for the production of [11C]raclopride routinely used in our PET center for human and animal studies,9, 10 and we are interested in the development of PET D3 receptor radioligands. (E)-4,2-Methoxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4-MMC, 1a, Ki/D3 0.38 nM, Ki/D2 12 nM, ratio D2/D3 32; 2-MMC, 1c, Ki/D3 0.56 nM, Ki/D2 14 nM, ratio D2/D3 25) are two new high-affinity D3 receptor antagonists recently developed by Hackling et al.1 Both compounds possess the combination of favorable pharmacokinetics and nanomolar Ki binding affinity for D3 receptor, and O-methyl positions amenable to labeling with carbon-11. These same properties are often beneficial in a diagnostic radiotracer. We investigated whether 11C-labeled analogs of 4-MMC and 2-MMC, (E)-4,2-[11C]methoxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-cinnamoylamides (4-[11C]MMC, [11C]1a; 2-[11C]MMC, [11C]1c), could be used to map brain D3 receptors in vivo. As part of our efforts to evaluate potential brain-imaging agents, we synthesized 4-[11C]MMC ([11C]1a); (E)-3-[11C]methoxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamide (3-[11C]MMC, [11C]1b); and 2-[11C]MMC ([11C]1c), and performed initial PET imaging studies of the tracers [11C]1a–c in rat brain.
Section snippets
Chemistry, radiochemistry, and lipophilicity
The synthetic approach for 4,3,2-[11C]MMCs ([11C]1a–c) is shown in Scheme 1.
The synthesis of the precursors (E)-4,3,2-hydroxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4,3,2-HMCs, 1d–f), and reference standards (E)-4,3,2-methoxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4,3,2-MMCs, 1a–c), as indicated in Scheme 1, was performed using a modification of the literature procedure.1 Commercially available N-(4-bromobutyl)phthalimide (2) was reacted with
Conclusion
The synthetic procedures that provide new tracers 4,3,2-[11C]MMCs have been well developed. The initial PET imaging studies of the tracers 4,3,2-[11C]MMCs showed that these three tracers had a certain uptake in the rat brain. Comparative studies of the images and the average intensity in the rat brain of 4,3,2-[11C]MMCs showed the brain uptake sequence was 4-[11C]MMC > 3-[11C]MMC > 2-[11C]MMC. However, the results from the blocking studies by intraperitoneal injection with pretreatment drugs
General
All commercial reagents and solvents were used without further purification unless otherwise specified. The [11C]methyl triflate was made according to the literature procedure.11 Melting points were determined on a MEL-TEMP II capillary tube apparatus and were uncorrected. 1H NMR spectra were recorded on a Bruker QE 300 NMR spectrometer using tetramethylsilane (TMS) as an internal standard. Chemical shift data for the proton resonances were reported in parts per million (δ) relative to the
Acknowledgments
This work was partially supported by the Indiana 21st Century Research and Technology Fund and the Indiana Genomics Initiative (INGEN) of Indiana University, which is supported in part by Lilly Endowment Inc. The authors would like to thank Winston Baity, Terry McBride, Tanya Martinez, and Kristan Boling for their assistances in animal studies, and Drs. Evan Morris and Karmen Yoder for their helpful advice on PET data analysis. The referee’s criticisms and editor’s comments for the revision of
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