Elsevier

Bioorganic & Medicinal Chemistry

Volume 13, Issue 22, 15 November 2005, Pages 6233-6243
Bioorganic & Medicinal Chemistry

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

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Abstract

D3 receptor radioligands (E)-4,3,2-[11C]methoxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4-[11C]MMC, [11C]1a; 3-[11C]MMC, [11C]1b; and 2-[11C]MMC, [11C]1c) were synthesized for evaluation as novel potential positron emission tomography (PET) imaging agents for brain D3 receptors. The new tracers 4,3,2-[11C]MMCs were prepared by O-[11C]methylation of corresponding precursors (E)-4,3,2-hydroxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4,3,2-HMCs) using [11C]methyl triflate and isolated by the solid-phase extraction (SPE) purification procedure with 40–65% radiochemical yields, decay corrected to end of bombardment (EOB), and a synthesis time of 15–20 min. The PET dynamic studies of the tracers [11C]1ac in rats were performed using an animal PET scanner, IndyPET-II, developed in our laboratory. The results show that the brain uptake sequence was 4-[11C]MMC > 3-[11C]MMC > 2-[11C]MMC, which is consistent with their in vitro biological properties. The initial PET blocking studies of the tracers 4,3,2-[11C]MMCs with corresponding pretreatment drugs (E)-4,3,2-methoxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4,3,2-MMCs, 1ac) had no effect on 4,3,2-[11C]MMCs-PET rat brain imaging. These results suggest that the localization of 4,3,2-[11C]MMCs in rat brain is mediated by nonspecific processes, and the visualization of 4,3,2-[11C]MMCs-PET in rat brain is related to nonspecific binding.

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.

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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]1ac in rat brain.

Section snippets

Chemistry, radiochemistry, and lipophilicity

The synthetic approach for 4,3,2-[11C]MMCs ([11C]1ac) 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, 1df), and reference standards (E)-4,3,2-methoxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4,3,2-MMCs, 1ac), 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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