Laboratory note
Synthesis of [11C]FEDAA1106 as a new PET imaging probe of peripheral benzodiazepine receptor expression

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Abstract

Peripheral benzodiazepine receptor (PBR) is associated with neuroinflammation and tumor progression. [11C]DAA1106 and [18F]FEDAA1106 are two promising radioligands for positron emission tomography (PET) imaging of PBR. This study was designed to develop a new radiolabeled analog of [11C]DAA1106 and [18F]FEDAA1106, [11C]FEDAA1106, for PET imaging of PBR expression in brain and cancer. Precursor N-(5-fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-hydroxybenzyl)acetamide (9) was synthesized in multiple steps with moderate to high chemical yields. Precursor 9 was labeled by [11C]CH3OTf and isolated by high pressure liquid chromatography (HPLC) purification to provide target radioligand N-(5-fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-[11C]methoxybenzyl)acetamide ([11C]FEDAA1106, [11C]10) in 60–70% radiochemical yields, decay corrected to end of bombardment (EOB), based on [11C]CO2. The specific activity of the target radiotracer [11C]10 was in a range of 111–185 GBq/μmol at the end of synthesis (EOS).

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This paper reports the synthesis of a new radioligand, [11C]FEDAA1106, for PET imaging of peripheral benzodiazepine receptor expression in brain and tumor.

Introduction

The peripheral benzodiazepine receptor (PBR) is a protein found in lung, liver, heart, spleen, kidney, adrenals, brain, glial cells, masts cell and macrophages and implicated in numerous nervous system disorders such as epilepsy, cerebral ischemia, nerve injury and neurodegenerative diseases, and immune system diseases such as cancer [1]. PBR is an attractive target for molecular imaging of neuroinflammation and tumor progression. There is great interest in imaging of PBR expression in human diseases such as Alzheimer's disease and neurofibromas [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. The high-affinity PBR ligands include new compounds with structural classes of isoquinoline carboxamides, quinoline carboxamides, benzothiazepines, benzoxazepines, indoleacetamides, pyrazolopyrimidines, vinca alkaloids, and aryloxyanilides [1]. These small molecule ligands may have high binding affinity but still lack specificity for the receptor due to non-specific interactions. Recently two acetamide parent compounds DAA1106 (N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide) and its derivative FEDAA1106 (N-(5-fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-methoxybenzyl)acetamide) were reported as potent and selective ligands for PBR and displayed high PBR binding affinities (Ki = 0.16 nM and 0.078 nM in rat brain sections, respectively) [19], [20], [21], [22]. Both ligands had more potent in vitro binding affinities for PBR than PK11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-isoquinoline-3-carboxamide), a standard ligand for PBR [23], [24]. Consequently, carbon-11 labeled analog of DAA1106, [11C]DAA1106 (N-(2-[11C]methoxy-5-methoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide) and fluorine-18 labeled analog of FEDAA1106, [18F]FEDAA1106 (N-(5-fluoro-2-phenoxyphenyl)-N-(2-(2-[18F]fluoroethoxy)-5-methoxybenzyl)acetamide), have been developed as two promising radioligands for positron emission tomography (PET) [22], [25], [26], [27], and the in vivo biological evaluation displayed high specific binding of both radioligands to PBR, which suggested both compounds have high specificity [25]. Previous results indicated [18F]FEDAA1106 has higher PBR affinity and specificity than [11C]DAA1106, but requires more complex radiosynthesis. Compared to fluorine-18 tracers (half-life 110 min), carbon-11 tracers (half-life 20 min) have some advantages in back-to-back same-day PET studies, such as avoiding movement of the subject from the PET scanner and performing another study within 2–3 h to explore drug effects at the first study. These advantages become very valuable in studying pharmacological or behavioral changes [28]. We are interested in the development of new PET PBR radioligands. This study was designed to develop a new analog radioligand of [11C]DAA1106 and [18F]FEDAA1106, [11C]FEDAA1106 (N-(5-fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-[11C]methoxybenzyl)acetamide, [11C]10), a carbon-11 labeled form of FEDAA1106, which will combine the advantages of both [11C]DAA1106 and [18F]FEDAA1106, for PET imaging of PBR expression in brain and tumor (Fig. 1). Here, we report the synthesis of [11C]FEDAA1106.

Section snippets

Chemistry

The chemistry is straightforward. Synthetic approach for phenolic precursor and standard compound FEDAA1106 is shown in Scheme 1, Scheme 2, Scheme 3.

As depicted in Scheme 1, the key intermediate 4 was prepared from commercially available 2,5-dihydroxybenzaldehyde. 2,5-Dihydroxybenzaldehyde was benzylated selectively using benzyl bromide in the presence of NaHCO3 and KI in CH3CN to obtain 5-monobenzylated compound 1 in 32% yield [29], [30], the slight selectivity is normally attributed to the

General

All commercial reagents and solvents from Aldrich and Sigma were used without further purification. [11C]CH3OTf was prepared according to a literature procedure [31]. Melting points were determined on a MEL-TEMP II capillary tube apparatus and were uncorrected. 1H NMR spectra were recorded on a Varian Gemini 2000 200 MHz FT-NMR and Bruker Avance II 500 MHz NMR spectrometer using tetramethylsilane (TMS) as an internal standard. Chemical shift data for the proton resonances were reported in parts

Conclusions

An efficient and convenient synthesis of new PET PBR radioligand [11C]FEDAA1106 has been well developed. The synthetic methodology employed classical organic chemistry such as benzylation, alkylation, reduction, bromination, acetylation, hydrogenation and methylation to prepare phenolic precursor and standard compound FEDAA1106. The target radioligand [11C]FEDAA1106 was prepared by O-[11C]methylation of its corresponding phenolic precursor using a reactive [11C]methylating agent, [11C]CH3OTf,

Acknowledgments

This work was partially supported by the Indiana Genomics Initiative (INGEN) of Indiana University, which is supported in part by Lilly Endowment Inc. The authors would like to thank Dr. Bruce H. Mock and Barbara E. Glick-Wilson for their assistance in production of [11C]CH3OTf. The referees' criticisms and editor's comments for the revision of the manuscript are greatly appreciated.

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