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. 2023 Sep 25;14(19):3694–3703. doi: 10.1021/acschemneuro.3c00382

Concise and Scalable Radiosynthesis of (+)-[18F]MDL100907 as a Serotonin 5-HT2A Receptor Antagonist for PET

Lahu N Chavan †,*, Ronald Voll †,‡,*, Mar M Sanchez ‡, Jonathon A Nye †,‡, Mark M Goodman †,‡,§,*
PMCID: PMC10557077  PMID: 37748194

Abstract

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5-Hydroxytryptamine (5-HT2A) receptors play an important role in several psychiatric disorders. In order to investigate the serotonin (5-HT) receptor in vivo, reliable syntheses are required for positron emission tomography (PET) 5-HT radioligands. Owing to the excellent in vivo properties of [18F]MDL100907 for PET, there has been great interest to develop a novel synthetic route for [18F]MDL100907. Here, we report a highly efficient, scalable, and expedient synthesis for [18F]MDL100907. The radiofluorination was performed on a 18F-labeling boron pinacol ester precursor, which is synthesized using the Liebeskind–Srogl cross-coupling reaction as a key step. Our method is practically more suitable to employ late-stage Cu-mediated radiofluorination and facilitate the production of the [18F]MDL100907 radioligand in excellent decay-corrected RCY of 32 ± 10% (n = 7) within 60 min. We prepared [18F]MDL100907 in high molar activity (2.1 Ci/μmol) and compared it to [11C]MDL100907 in the brain of a nonhuman primate.

Keywords: 5-HT2A, radiofluorination, copper catalysis, Liebeskind−Srogl reaction

Introduction

In the brain, serotonin, or 5-hydroxytryptamine (5-HT), is released from serotonergic fibers that originate in the raphe nuclei and innervate cortical and limbic structures of the medial temporal lobe system.1−3 Serotonin receptors are an important neurotransmitter in the central nervous system (CNS) and peripheral tissues, which play a crucial role in the pathophysiology of several neuropsychiatric disorders. There are seven major families of transmembrane receptors (5-HT1–7), and one transporter is known to control 5-HT function.4,5 Literature findings indicate that serotonergic 5-HT2A receptors, which are widely expressed in cortical and forebrain regions, may be related to or contribute to neuropsychiatric disorders, such as schizophrenia, major depressive disorder, bipolar disorder, and cognitive disturbances associated with Alzheimer’s or Parkinson’s disease.6−9 Serotonergic 5-HT2A receptors are of central interest in the quantification of receptor densities and measurement of receptor occupancy in the human brain to understand the biological principles of the mentioned disorders and contribute to the development of appropriate therapies.10−15 To quantify 5-HT2A receptors in vivo, molecular imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography, can be used. There have been large efforts done to develop selective and high-affinity radiolabeled ligands for PET-based visualization of 5-HT2A, of which [11C]MDL100907 or [18F]MDL100907 and [18F]altanserin proved to be the most useful (Figure 1).16−24

Figure 1.

Figure 1

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PET-based radioligands.

In vivo studies of both [11C]MDL100907 and [18F]altanserin tracers showed high affinity and selectivity for 5-HT2A receptors. However, [18F]altanserin metabolizes rapidly and forms at least four metabolites, which penetrate the BBB and hinder the measurement of uptake kinetics in the brain.25 Additionally, [18F]altanserin shows off-target binding to receptors outside the serotonergic system. On the other hand, MDL100907 undergoes extensive first-pass metabolism, and the major metabolites of MDL100907 do not enter the brain to any large extent.26−28 Thus, the [11C]MDL100907- and [18F]MDL100907-labeled tracers have been synthesized and used in PET imaging. In 1999, Mathis et al. reported the 11C-labeling of MDL100907 in two specific positions.26 But the major drawback of [11C]MDL100907 is its short half-life (20 min), which makes it difficult to measure the binding of ligands during late time points (≥90 min) before the ligand equilibrates between blood and tissue.29,31

Apart from [11C]MDL100907, a radioligand [18F]MDL100907 with a more suitable half-life has been synthesized by Mühlhausen and co-workers.30 However, the complex labeling step involved a sequential four-step reaction sequence with 120 min of reaction time, which ended with a low (1–2%) radiochemical yield (Scheme 1). Recently, Ritter et al. demonstrated the Ni-mediated oxidative fluorination for the synthesis of [18F]MDL100907.31 The reaction sequence involved in this protocol is a one-pot two-step process. Initially, the precursor 2 was labeled with 18F, which was then assembled with an excess of chiral amine 1 to offer desired [18F]MDL100907 in a 3% non-decay-corrected yield (Scheme 1).

Scheme 1. Previous and Present Approaches.

Scheme 1

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Here, we report a novel synthetic strategy for producing [18F]MDL100907 in high RCY32 through a late-stage Cu-mediated radiofluorination reaction. The resulted [18F]MDL100907 was evaluated against [11C]MDL100907 for reliability to quantify 5-HT2A in the nonhuman primate brain. For this endeavor, we have chosen the classical Liebeskind–Srogl cross-coupling reaction as the key transformation for the scalable synthesis of compound 6.

Results and Discussion

Our synthetic strategy of 6 depicted in Scheme 2 relied on a copper-mediated palladium-catalyzed Liebeskind–Srogl cross-coupling reaction of thioester derivative 4 and boronic acid 5 under neutral conditions.33,34 In our attempt to synthesize compound 6 in quantitative yield, we have optimized the reaction conditions using different copper complexes (Table 1). In this cross-coupling, copper(I) diphenylphosphinate (CuDPP) was the best Cu(I) carboxylate complex, giving a high yield of ketone product.

Scheme 2. Synthesis of (±) MDL100907 and Iodo-Analogue.

Scheme 2

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Table 1. Screening for Optimal Reaction Conditionsa,b.

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entry Cu(I) time (h) yield
1 CuTC 4.5 76
2 CuDPP 4.5 93
3 CuMeSal 4.5 81
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a

Standard reaction conditions: The reaction was carried out with 4 (1 mmol), 5 (2 mmol), Pd(dba)3 (0.025 mmol) Cu(I) (1.5 mmol), and P(OEt)3 (0.2 mmol) in solvent (0.1 M).

b

Yield of the isolated product.

Briefly, the synthesis commenced with the coupling of commercially available acid 3 with p-toluene thiophenol using dicyclohexylcarbodiimide (DCC) at room temperature resulting in corresponding thioester 4 in a 96% yield.35 With an appropriate precursor in hand, we next investigated the Liebeskind–Srogl cross-coupling reaction of thioester 4 and boronic acid 5 with various copper reagents, such as copper(I) thiophene-2-carboxylate (CuTC), CuDPP, and copper(I) methylsalicylate (CuMeSal), using a catalytic amount of Pd(dba)3 in THF solvent at room temperature (RT). To our delight, CuDPP was found to be the better reagent to yield a key ketone product in 93% yield.

In the next synthetic step, the removal of the piperidine Boc group with TFA produced 7 in 83% yield. The free amine 7 was subsequently coupled with 4-iodophenylethyl bromide 8a (prepared by the reaction of 4-iodophenylethyl alcohol with PBr3 in dichloromethane) and 4-fluorophenylethyl bromide 8b, which provided 9 and 10 in 91 and 89% yields, respectively. The ketone groups in 9 and 10 were reduced using NaBH4 in methanol, which provided racemic (±) MDL100907 (11) and iodo-derivative 12 in high yield (Scheme 2).

The racemic alcohol 12 was derivatized with chiral (s)-(+)-α-methoxyphenylacetic acid to afford two diastereomers in 93% yield (14a, 14b in 1:1 ratio), which were easily separated by column chromatography. The radiolabeling precursor 15 was synthesized from the required diastereomer 14a by a Miyaura borylation reaction using bispinacolatodiboron and Pd(dppf)Cl2 in 85% yield after purification.36 Thus, this multistep procedure proved successful and allowed us to synthesize the desired borylated precursor on a gram scale (Scheme 3).

Scheme 3. Synthesis of Pinacol Boron Ester Precursor.

Scheme 3

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Having synthesized borylated precursor 14a, we next focused on exploring the copper-mediated oxidative 18F-fluorination reaction.37−39 Typically, the most common catalytic condition used in oxidative 18F-fluorination is Cu(OTf)2(py)440−43 either in DMA or DMF as the solvent at 120 °C temperature for 20 to 30 min to acquire better conversion.44 Initially, we attempted direct radiofluorination on 15 using remote semiautomated synthesis in a Siemens Computer Programmable Chemical Unit (CPCU) using DMA at 110 °C, followed by deprotection of the ester group (aq 1 N NaOH, 10 min at 120 °C) furnished [18F]MDL100907 in low radiochemical yield, RCY = 1% along with protodeboronation.45 This was circumvented by heating the reaction mixture at 120 °C, where [18F]MDL100907 was obtained in RCY = 3–6% (n = 6). Surprisingly, we did not observe any protodeboronation product during high-performance liquid chromatography (HPLC) purification, but the yield of the reaction was not satisfactory. Anticipating a better yield, we used nBuOH as a co-solvent along with DMA; to our delight, the reaction yield was increased substantially, and we obtained [18F]MDL100907 in 32 ± 10% (n = 7). Eventually, the pinacol ester 15 was radiofluorinated using the Cu(II) catalyst with subsequent deprotection of the ester group using 1 M NaOH as the base, followed by HPLC purification that required only 60 min (Scheme 4).46 The enantiomeric purity (ee) of the final product was 92.61 ± 0.64% (n = 2) checked after the basic hydrolysis of ester, as shown in Figures S20–S22.

Scheme 4. Cu-Mediated Late-Stage Radiolabeling,

Scheme 4

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Reaction conditions: The reaction was carried out with 15 (1.5 mmol), Cu(OTf)2(py)4 (3.1 mmol), fluoride source, and TEABC (1.5 mg) in DMA/nBuOH (300/100 μL).

Decay-corrected radiochemical yields of products isolated after HPLC purification.

The microPET images for a 120 min study with [18F]MDL100907 in an adult male rhesus monkey and in comparison with [11C]MDL100907 for a 90 min study taken in the same male rhesus monkey 3 years earlier are shown in Figure 2. The time–activity curves (TACs) for [18F]MDL100907 and [11C]MDL100907 are shown in Figures S24 and S25, respectively. As shown in Figures S24 and S25, high uptake of radioactivity is observed in the regions of the brain known to have a high 5-HT2a density.27

Figure 2.

Figure 2

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5-HT2A distribution microPET brain uptake.

In conclusion, a flexible and scalable synthetic route to MDL100907 and precursor for radiosynthesis of [18F]MDL100907 15 has been developed using the Liebeskind–Srogl cross-coupling reaction as a key step to introduce the aryl ketone moiety. Our method is practically more suitable to employ late-stage Cu-mediated radiofluorination and facilitate the production of [18F]MDL100907 in excellent DCRCY of 32 ± 10% (n = 7) within 60 min, 92.61% ee with high molar activity (2.1 Ci/μmol) (see the Supporting Information). As demonstrated by our initial finding, [18F]MDL100907 provides a comparable 5-HT2A distribution to [11C]MDL100907 as shown in Figure 2. Repetitive scans and analyses with [18F]MDL100907 are in progress to demonstrate the robustness of this method for translation to human imaging for clinical neuroscience research.

Materials and Methods

General Information

All solvents were purchased from Fisher Scientific or Sigma-Aldrich and dried over 4 Å molecular sieves (8–12 mesh, Sigma-Aldrich). Unless otherwise noted, all commercially available reagents and substrates were used directly as received. Thin-layer chromatography was performed on Merck silica gel plates and visualized by ultraviolet (UV) light and/or potassium permanganate. 1H, 13C, and 19F NMR spectra were recorded on Bruker 300, Varian INOVA 600, INOVA 500, and INOVA 400 spectrometers. Residual solvent resonances were treated as internal reference signals. 19F spectra were referenced to either trifluoroacetic acid (−76.55 ppm) or fluorobenzene (−113.15 ppm). IR spectra were recorded on a Nicolet iS10 Fourier-transform infrared (FTIR) spectrometer, and the absorption peaks were reported in cm–1. The purification of products was performed via flash chromatography, unless otherwise noted. High-resolution mass spectra were obtained from the Emory University Mass Spec Facility Inc. The [18F]fluoride was produced at the Emory University Center for Systems Imaging with an 11 MeV Siemens RDS 111 negative-ion cyclotron (Knoxville, TN) by the 18O(p,n) 18F reaction using [18O]H2O (95%). Alumina N SepPaks and HLB Oasis cartridges were purchased from Waters, Inc. (Milford, MA). Radiometric TLC was performed with the same type of silica plates from Whatman and analyzed using a Raytest system (Rita Star, Germany). Isolated radiochemical yields were determined using a dose calibrator (Capintec CRC-712M). Analytical HPLC experiments were performed with a Waters Breeze HPLC system equipped with a Bioscan flowcount radioactivity detector and an inline UV detector set to monitor wavelengths 210, 230, and 254 nm (Astec chirobiotic T column, Sigma-Aldrich part number 12021AST; mobile phase: MeOH). All animal experiments were carried out under humane conditions and were approved by the Institutional Animal Use and Care Committee (IUCAC) and Radiation Safety Committees at Emory University.

General Procedure for the Synthesis of tert-Butyl 4-((p-tolylthio)carbonyl)piperidine-1-carboxylate (4)

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To a stirred solution of Boc-Inp-OH 3 (10 g, 43.6 mmol, 1 equiv) and 4-methylbenzenethiol (8.1 g, 65.5 mmol, 1.5 equiv) in dry ethyl acetate (0.1 M) at 0 °C were added N,N′-dicyclohexylcarbodiimide (9.8 g, 47.9 mmol, 1.1 equiv) and HOBt (7.7 g, 65.4 mmol, 1.5 equiv) under a N2 atmosphere. The reaction was stirred at 0 °C for the first 30 min and then at room temperature overnight. After completion of the reaction, a few drops of 50% acetic acid in ethyl acetate was added and the reaction mixture was filtered through a pad of celite. The filtrate was dried over Na2SO4, and the solvent was removed under reduced pressure and the crude reaction mixture was purified by column chromatography on silica gel to afford 3 as a white solid (14 g, 96% yield). Rf = 0.3 (EtOAc/hexane, 7:3); 1H NMR (300 MHz, CDCl3) δ 7.32–7.14 (m, 4H), 4.09 (d, J = 11.1 Hz, 2H), 2.90–2.63 (m, 3H), 2.35 (s, 3H), 1.93 (d, J = 10.9 Hz, 2H), 1.79–1.61 (m, 2H), 1.45 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 199.8, 154.6, 139.7, 135.2–133.7 (m), 130.8–129.1 (m), 123.7, 79.7, 50.0 (d, J = 34.5 Hz), 44.1–42.0 (m Hz), 29.6–27.2 (m), 21.3 (d, J = 12.0 Hz); high-resolution mass spectrometry (HRMS) (ESI) calcd for C21H14O2 [M + H]+: 299.1072; found: 299.1084.

General Procedure for the Synthesis of tert-Butyl 4-(2,3-dimethoxybenzoyl)piperidine-1-carboxylate (6)

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General Procedure for the Liebeskind–Srogl Cross-Coupling Reaction

A mixture of N-Boc-piperidine-Phe-SPh (12.7 g, 38.0 mmol, 1 equiv), 2, 3-dimethoxylphenylboronic acid (13.8 g, 76.1 mmol, 2.0 equiv), CuDPP (10.8 g, 57.0 mmol, 1.5 equiv), and Pd2(dba)3 (0.869 g, 0.025 mmol, 0.025 equiv) was placed under an argon atmosphere. THF (110 mL, degassed and dried over 4 Å molecular sieves) and triethylphosphite (1.2 g, 7.6 mmol, 0.2 equiv) were added, and the mixture was stirred at room temperature until the N-Boc-piperidine-Phe-SPh ester was consumed (∼3 h). Reaction progress was monitored by TLC. The reaction mixture was diluted with ether (200 mL), washed with aq NaHCO3 (200 mL ×2) solution and brine (150 mL), and then dried over Na2SO4. The drying agent was filtered off through a short plug of silica gel (to aid removal of metal-containing products) and concentrated under vacuum using a rotary evaporator. The crude product was purified on silica gel column chromatography to give the insertion product 6 as a pale oil (12.2 g, 93% yield). Rf = 0.3 (EtOAc/hexane, 6:4); 1H NMR (300 MHz, CDCl3) δ 7.13–6.86 (m, 3H), 4.14–3.95 (m, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.20 (tt, J = 11.0, 3.7 Hz, 1H), 2.79 (t, J = 11.5 Hz, 2H), 1.81 (dd, J = 13.2, 2.6 Hz, 2H), 1.63–1.44 (m, 3H), 1.41 (s, 9H).; 13C NMR (75 MHz, CDCl3) δ 206.0, 154.7 (d, J = 6.2 Hz), 154.2, 152.7, 151.5 (d, J = 9.6 Hz), 146.9, 134.0, 128.2–127.1 (m), 125.0–124.1 (m), 120.5–120.0 (m), 116.2–114.7 (m), 79.5, 61.4 (dd, J = 30.0, 14.6 Hz), 57.0–55.4 (m), 48.0, 44.0–42.5 (m), 28.4, 28.3, 27.8.

General Procedure for the Synthesis of (2,3-Dimethoxyphenyl)(piperidin-4-yl)methanone (7)

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The 4-(2,3-bismethoxy-benzoyl)-1-piperidinecarboxylic acid t-butyl ester (10 g, 28.6 mmol) was dissolved carefully and gradually into trifluoroacetic acid (100 mL). The mixture was stirred at room temperature for 2 h. After that, the reaction mixture was diluted with 50 mL of ether and neutralized carefully with NH4OH while maintaining cooling in an ice bath. The layers were separated, and the aqueous layer was extracted with ether (3 × 50 mL). The combined organic extracts were washed with water (50 mL), dried over Na2SO4, filtered the combined organic extracts, and evaporated to afford a crude viscous brown oil (5.9 g, 83% yield). Rf = 0.2 (20%, CHCl3/MeOH = 8:2); 1H NMR (75 MHz, CD3OD) δ 7.23–7.03 (m, 2H), 6.97–6.91 (m Hz, 1H), 3.89–3.85 (m, 3H), 3.85–3.83 (m, 3H), 3.28–3.15 (m Hz, 1H), 3.11–2.97 (m Hz, 2H), 2.69–2.55 (m Hz, 2H), 1.88–1.75 (m Hz, 2H), 1.62–1.44 (m Hz, 2H). 13C NMR (75 MHz, CD3OD) δ 206.5, 152.8, 146.9, 133.8, 124.3 (d, J = 36.8 Hz), 119.9 (d, J = 34.9 Hz), 114.9 (d, J = 33.8 Hz), 60.5 (d, J = 22.8 Hz), 54.9 (d, J = 23.0 Hz), 45.0 (t, J = 24.3 Hz), 28.5–27.7 (m).

(2,3-Dimethoxyphenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanone (9)

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To a stirred suspension of (2,3-dimethoxyphenyl)(piperidin-4-yl)methanone 7 (100 mg, 0.4 mmol, 1 equiv) and NaHCO3 (50 mg, 0.6 mmol, 1.5 equiv) in DMF (0.2 mL) was added 1-(2-bromoethyl)-4-iodobenzene (98 mg, 4.8 mmol, 1.2 equiv) under a N2 atmosphere, and the reaction mixture was heated at 85 °C for 90 min. After the starting material disappeared, the reaction mixture was cooled to room temperature and water was added. Then, the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 9 as a colorless oil (133 g, 89% yield). Rf = 0.3 (EtOAc/hexane, 6:4); 1H NMR (300 MHz, CDCl3) δ 7.17–7.04 (m, 3H), 7.02–6.89 (m, 4H), 3.87 (s, 3H), 3.85 (s, 3H), 3.07 (tt, J = 11.0, 3.9 Hz, 1H), 2.96 (dt, J = 11.4, 3.2 Hz, 2H), 2.80–2.71 (m, 2H), 2.58–2.48 (m, 2H), 2.10 (td, J = 11.4, 2.5 Hz, 2H), 1.96–1.84 (m, 2H), 1.81–1.65 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 206.4, 162.9, 159.7, 152.7, 146.9, 136.0, 134.3, 130.8–130.0 (m), 124.6 (d, J = 39.2 Hz), 120.5 (d, J = 39.1 Hz), 116.2–113.6 (m), 61.6 (d, J = 23.8 Hz), 60.7, 55.8 (d, J = 23.5 Hz), 53.1 (d, J = 31.4 Hz), 47.9 (d, J = 24.9 Hz), 33.5–32.2 (m), 28.7–27.4 (m) 19F NMR (376 MHz, CDCl3) δ −185.1.

(2,3-Dimethoxyphenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanol [(±)MDL100907] (11)

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To a stirred solution of (2,3-dimethoxyphenyl)[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl] methanone 9 (100 mg, 0.26 mmol, 1 equiv) in MeOH (0.2 mL) at 0 °C was added NaBH4 (20 mg, 0.53 mmol, 2 equiv) in two portions, over a one hour period. The reaction mixture was slowly warmed to room temperature and stirred overnight. After completion of the reaction, the solvent was removed under vacuum. The residue was dissolved in water (5 mL) and extracted with Et2O (3 × 10 mL). The combined organic layer was dried using Na2SO4, filtered, and then concentrated under vacuum. The crude reaction mixture was purified by column chromatography to give (±) MDL100907 as a white solid (82 mg, 82% yield). Rf = 0.3 (EtOAc/hexane, 5:5); 1H NMR (300 MHz, CDCl3) δ 7.16–7.09 (m, 2H), 7.07–6.99 (m, 1H), 6.98–6.88 (m, 3H), 6.83 (dd, J = 8.1, 1.5 Hz, 1H), 4.66 (d, J = 7.5 Hz, 1H), 3.85 (s, 6H), 3.17 (d, J = 12.5 Hz, 1H), 3.04 (d, J = 11.2 Hz, 1H), 2.84 (dd, J = 10.6, 5.7 Hz, 2H), 2.63 (dd, J = 10.2, 6.2 Hz, 2H), 2.19–1.99 (m, 3H), 1.79–1.43 (m, 3H), 1.40–1.29 (m Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 163.0, 159.8, 152.4, 146.3, 136.2, 135.1, 129.8 (d, J = 43.9 Hz), 123.7 (d, J = 41.7 Hz), 119.8 (d, J = 37.3 Hz), 116.0–114.0 (m), 112.4–110.2 (m), 75.0–72.5 (m), 61.2–59.3 (m), 55.8 (d, J = 23.5 Hz), 54.7–52.5 (m), 42.8–41.8 (m), 32.1, 28.4–27.6. 19F NMR (376 MHz, CDCl3) δ −104.19, −172.21.

(2,3-Dimethoxyphenyl)(1-(4-iodophenethyl)piperidin-4-yl)methanone (10)

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To a stirred suspension of (2,3-dimethoxyphenyl)(piperidin-4-yl)methanone 7 (1 g, 4.0 mmol, 1 equiv) and NaHCO3 (500 mg, 6 mmol, 1.5 equiv) in DMF (5 mL) was added 1-(2-bromoethyl)-4-iodobenzene (1.5 g, 4.8 mmol, 1.2 equiv) under a N2 atmosphere, and the reaction mixture was heated at 85 °C for 90 min. After the starting material disappeared, the reaction mixture was cooled to room temperature and water was added. Then, the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 10 as a colorless oil (1.7 g, 91% yield). Rf = 0.3 (EtOAc/hexane, 7:3); 1H NMR (300 MHz, CDCl3) δ 7.61–7.54 (m, 2H), 7.12–6.91 (m, 5H), 3.89 (s, 3H), 3.85 (s, 3H), 3.08 (tt, J = 10.9, 3.9 Hz, 1H), 2.96 (dt, J = 11.5, 3.3 Hz, 2H), 2.77–2.69 (m, 2H), 2.59–2.49 (m, 2H), 2.11 (td, J = 11.4, 2.5 Hz, 2H), 1.95–1.85 (m, 2H), 1.81–1.65 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 206.4, 152.7, 146.9, 140.1, 137.4 (d, J = 9.8 Hz), 134.3, 130.7 (d, J = 21.9 Hz), 124.5 (d, J = 24.0 Hz), 120.1 (d, J = 25.2 Hz), 114.9 (d, J = 25.2 Hz), 91.1, 61.9 (d, J = 20.0 Hz), 60.3, 56.0 (d, J = 20.3 Hz), 53.1 (d, J = 19.1 Hz), 48.1 (d, J = 14.3 Hz), 33.1, 28.0.

(2,3-Dimethoxyphenyl)(1-(4-iodophenethyl)piperidin-4-yl)methanol (12)

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To a stirred solution of (2,3-dimethoxyphenyl) (1-(4-iodophenethyl)piperidin-4-yl)methanone 11 (1.5 g, 3.1 mmol, 1 equiv) in MeOH (2 mL) at 0 °C was added NaBH4 (0.230 g, 6.2 mmol, 2 equiv) in two portions, over a 1 h period. The reaction mixture was slowly warmed to room temperature and stirred overnight. After completion of the reaction, the solvent was removed under vacuum. The residue was dissolved in water (5 mL) and extracted with Et2O (3 × 100 mL). The combined organic layer was dried using Na2SO4, filtered, and then concentrated under vacuum. The crude reaction mixture was purified by column chromatography to give 12 as a colorless oil (1.2 g, 80% yield). Rf = 0.3 (EtOAc/hexane, 5:5); 1H NMR (300 MHz, CDCl3) δ 8.09–7.98 (m, 2H), 7.57–7.44 (m, 1H), 7.44–7.26 (m, 4H), 5.08 (d, J = 7.6 Hz, 1H), 4.36–4.30 (m, 6H), 3.51 (d, J = 10.0 Hz, 1H), 3.36 (d, J = 10.7 Hz, 1H), 3.28–3.13 (m, 2H), 3.06–2.90 (m, 2H), 2.53 (d, J = 13.1 Hz, 1H), 2.48–2.27 (m, 3H), 2.02–1.69 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 152.9, 146.9, 140.6, 137.9 (d, J = 4.0 Hz), 137.7, 136.8, 132.0–130.5 (m), 125.0–123.7 (m), 120.6–119.3 (m), 111.6 (d, J = 24.0 Hz), 91.4, 74.8 (q, J = 47.3 Hz), 61.7–60.4 (m), 56.0 (d, J = 11.8 Hz), 54.1, 43.2, 33.7, 29.2.

(R)-(2,3-Dimethoxyphenyl)(1-(4-iodophenethyl)piperidin-4-yl)methyl 2-methoxy-2-phenylacetate (14a)

graphic file with name cn3c00382_0017.jpg

(2,3-Dimethoxyphenyl)(1-(4-iodophenethyl)piperidin-4-yl)methanol 12 (0.832 g, 1.7 mmol, 1 equiv) was dissolved in CHCl3 (10 mL) and added (S)-(+)-methoxyphenylacitic acid (0.287 g, 1.7 mmol, 1 equiv), dicyclohexylcarbodiimide (DCC) (0.350 g, 1.7 mmol, 1 equiv), and 4-N,N-dimethylaminopyridine (DMAP) (20 mg, 0.17 mmol, 0.1 equiv) sequentially under N2 at room temperature. The reaction mixture was stirred at 68 °C for 15 h, cooled to room temperature, and filtered. The solid was rinsed with ether. The filtrate was collected and concentrated under vacuum. The crude diastereomers were separated by column chromatography. The fraction containing the first-eluting diastereomeric ester was combined and evaporated to give 14a as a white solid (500 mg, 42% yield). Rf = 0.5 (EtOAc/hexane, 5:5); 1H NMR (300 MHz, CDCl3) δ 7.58–7.52 (m, 2H), 7.48–7.42 (m, 2H), 7.40–7.31 (m, 3H), 6.97 (t, J = 8.0 Hz, 1H), 6.93–6.86 (m, 2H), 6.78 (ddd, J = 14.2, 8.0, 1.4 Hz, 2H), 5.90 (d, J = 8.3 Hz, 1H), 4.75 (s, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 3.35 (s, 3H), 2.79 (d, J = 11.5 Hz, 2H), 2.64 (dd, J = 10.0, 6.0 Hz, 2H), 2.42 (dd, J = 9.7, 6.3 Hz, 2H), 1.84–1.72 (m, 2H), 1.71–1.58 (m, 1H), 1.44–1.26 (m, 2H), 1.25–1.01 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.0, 152.4, 146.5, 140.1, 137.4, 137.2, 136.3, 132.9, 130.6 (d, J = 28.4 Hz), 128.7 (d, J = 8.5 Hz), 128.4 (d, J = 8.5 Hz), 127.1 (d, J = 21.5 Hz), 124.1 (d, J = 30.2 Hz), 118.7 (d, J = 22.2 Hz), 111.6 (d, J = 25.0 Hz), 91.0, 82.9 (q, J = 44.8 Hz), 75.0 (d, J = 23.2 Hz), 60.8–59.8 (m), 57.3 (t, J = 54.9 Hz), 55.5 (d, J = 22.6 Hz), 53.2 (d, J = 13.1 Hz), 41.0 (d, J = 15.1 Hz), 33.1, 27.4 (d, J = 42.4 Hz); HRMS (ESI) calcd for C31H36INO5 [M + H]+: 630.17184; found: 630.17117.

(S)-(2,3-Dimethoxyphenyl)(1-(4-iodophenethyl)piperidin-4-yl)methyl 2-methoxy-2-phenylacetate (14b)

graphic file with name cn3c00382_0018.jpg

14b as a white solid (500 mg, 42% yield). Rf = 0.4 (AcOEt/hexane, 5:5); 1H NMR (300 MHz, CDCl3) δ 7.59–7.53 (m, 2H), 7.39–7.29 (m, 5H), 6.94–6.89 (m, 2H), 6.72–6.64 (m, 2H), 6.12 (dd, J = 6.5, 2.8 Hz, 1H), 5.94 (d, J = 6.8 H, 1H), 4.80 (s, 3H), 3.86 (s, 1H), 3.79 (s, 3H), 3.39 (s, 3H), 2.93 (t, J = 11.7 Hz, 2H), 2.70 (dd, J = 10.3, 5.7 Hz, 2H), 2.49 (dd, J = 9.9, 6.3 Hz, 2H), 1.96–1.80 (m, 2H), 1.70 (d, J = 8.7 Hz, 2H), 1.54–1.31 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 169.7, 152.2, 146.1, 140.0, 137.4 (d, J = 11.6 Hz), 136.0, 132.6, 131.1, 130.5, 129.2–128.6 (m), 128.5–127.8 (m), 127.6–126.8 (m), 124.5–122.4 (m), 118.2 (d, J = 30 Hz), 112.0–110.1 (m), 91.08, 82.7 (d, t = 40 Hz), 74.5 (d, J = 25 Hz), 60.5–59.7 (m), 57.3 (d, t = 52 Hz), 55.7 (d, J = 24.3 Hz), 54.2–52.6 (m), 41.4–40.5 (m), 33.8–32.7 (m), 28.3–27.3 (m).

(R)-(2,3-Dimethoxyphenyl)(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl) piperidin-4-yl)methyl(S)-2-methoxy-2-phenylacetate (15)

graphic file with name cn3c00382_0019.jpg

(1,1′-Bis(diphenylphosphino)ferrocene)-palladium(II) dichloride (6 mg, 0.02 mmol, 0.03 equiv) was added to a degassed (15 min nitrogen bubbling) mixture of 14a (0.600 g, 0.9 mmol, 1 equiv), bispinacolatodiboron (50 mg, 0.2 mmol, 1.1 equiv), and potassium acetate (52 mg, 0.5 mmol, 1.3 equiv) in DMF (10 mL). The reaction mixture was stirred for 3 h at 80 °C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, quenched with brine, and extracted with ethyl acetate (3 × 100). The organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting crude reaction mixture was purified by column chromatography (SiO2 was neutralized with Et3N before loading the crude mixture). After concentration under reduced pressure, the precursor 15 was isolated as a tan solid (0.510 g, 85% yield). Rf = 0.3 (DCM: MeOH, 8: 2); 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 2H), 7.49–7.42 (m, 2H), 7.40–7.31 (m, 3H), 7.19–7.13 (m, 2H), 7.01–6.93 (m, 1H), 6.78 (ddd, J = 15.1, 8.0, 1.4 Hz, 2H), 5.89 (d, J = 8.2 Hz, 1H), 4.75 (s, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.36 (s, 3H), 2.82 (d, J = 11.0 Hz, 2H), 2.73 (dd, J = 9.9, 6.3 Hz, 2H), 2.47 (dd, J = 9.9, 6.3 Hz, 2H), 1.85–1.73 (m, 2H), 1.72–1.62 (m, 1H), 1.44–1.35 (m, 2H), 1.32 (s, 12H), 1.21–1.12 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 170.0, 152.4, 146.6, 143.9, 136.3, 134.9, 133.0, 129.2–128.2 (m), 127.9, 127.4, 127.1, 124.3–123.6 (m), 118.7 (d, J = 20 Hz), 111.6 (d, J = 22.8 Hz), 83.6, 83.5, 82.9, 82.6, 75.2–74.6 (m), 60.3 (d, J = 22.0 Hz), 57.3 (t, J = 22.8 Hz), 55.5 (d, J = 22.0 Hz), 53.8–52.6 (m), 41.2 (d, J = 15.0 Hz), 33.8, 28.3–27.1 (m), 25.11, 24.93, 24.73, 24.54.; HRMS (ESI) calcd for C37H48BNO7 [M + H]+: 629.36329; found: 629.36401.

Radiochemistry

graphic file with name cn3c00382_0020.jpg

To a glass vessel containing a solution of MeCN (1.0 mL), was eluted 18F-fluoride 18.5 Bq (∼0.500 Ci) from an anion-exchange resin (QMA cartridge, 46 mg) with a solution of Et4NHCO3 (1.5 mg) in H2O (600 μL). The solvent was removed at 120 °C with a nitrogen flow, and additional MeCN (3.5 mL) was added, followed by evaporation of the solvent with a nitrogen flow to remove residual H2O. A solution of precursor 15 (10 mg, 10 μmol) and Cu(OTf)2(py)4 (21 mg, 10 μmol) in DMA/nBuOH (300/100 μL) was added, and the reaction mixture was heated at 120 °C for 20 min with stirring under air in a capped vial. Thereafter, the reactor was cooled to ∼40 °C and 0.5 mL of 1 M sodium hydroxide was added, and the mixture was allowed to react for 15 min at 120 °C. The mixture was then diluted with 6 mL of eluent (50%, H2O/EtOH, 0.1% TEA) and purified by prep HPLC (waters X Terra Prep RP18, 5 μm, 19 mm × 100 mm column) using water/EtOH/Et3N 50:50:0.01 (v/v/v) flow rate: 6 mL/min; tR = 15.5 min. The collected fraction was diluted with enough water to reduce the total concentration of organic solvent below 10%. The solution was then loaded onto a preconditioned Sep-Pak C18 cartridge, which was washed with water (10 mL) and briefly dried by a steam of argon before the product was eluted with 1.5 mL of EtOH into dose vials containing 13.5 mL of saline and was ready for microPET studies. Evidence of the identity of [18F]MDL100907 was achieved by comparing the Rf of the radioactive product with the Rf of the authentic cold compound [19F]MDL100907 on analytical HPLC (waters X Terra Prep RP18, 5 μm, 7.8 mm × 100 mm column) using the solvent system water/EtOH/Et3N 50:50:0.01 (v/v/v); flow rate: 2 mL/min; tR = 8 min (see Figures S2–S15). The pH of the final dose solution was tested with pH paper and found to be 6–7. The isolated radiochemical yield was 4 Bq (150 mCi) in 15 mL of 10% EtOH/saline as determined using a dose calibrator, affording a 32% decay-corrected radiochemical yield based on a synthesis time of approx. 60 min, which proceeded immediately upon the end of the cyclotron bombardment (Scheme 1).

Nonhuman Primate Imaging

The microPET study was performed using an adult male rhesus monkey. All protocols, animal care, and handling followed the National Institutes of Health Guide for the Care and Use of Laboratory Animals (8th edition, revised 2011) and the recommendations of AAALAC International and were approved by Emory University’s Institutional Animal Care and Use Committee (IACUC). The animal was fasted for 12 h prior to the PET study. The animals were initially anesthetized with an intramuscular injection of Telazol (3 mg/kg), intubated, and then maintained on a 1% isoflurane/5% oxygen gas mixture throughout the imaging session. [18F]MDL100907 was injected via the antecubital vein over the course of 5 min. Quantitative brain image studies were performed using a Siemens MicroPET Focus 220 scanner. A transmission scan was obtained with a germanium-68 source prior to the PET study for attenuation correction of the emission data. The scan was conducted following the injection of [18F]MDL100907. Emission data were collected continuously in list mode for 120 min after injection of [18F]MDL100907 and then rebinned into a 24-frame dynamic sequence for analysis.

The same animal underwent two PET neuroimaging studies acquired on a microPET focus 220 scanner system (CTI Concorde Microsystems LLC, Knoxville, TN). Animal anesthesia (isoflurane 1–2% to effect) and monitoring followed standard veterinary practices approved by Emory’s Institutional Animal Care and Use Committee (IACUC). In Nov. 2015, 2.9 mCi of [11C]MDL100907 was administered intravenously over one minute beginning simultaneously with a 90 min PET emission scan. Later, in Dec. 2021, 5.5 mCi of [18F]MDL100907 was administered intravenously over one minute beginning simultaneously with a 120 min PET emission scan. PET emission data were binned into individual frames and reconstructed. Time–activity curves were generated for regions in the frontal cortex and mid-brain areas using in-house templates developed for rhesus macaques.

Acknowledgments

The authors thank Eddy Ortega and Dr. Jaekeun Park for their contributions to the microPET studies, and Ron Crowe, BCNP, and the Radiopharmacy at the Emory University Center for Systems Imaging for production of 18F-fluoride.

Data Availability Statement

The data will be available upon request.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.3c00382.

  • Copies of 1H NMR, 13C NMR, and 19F NMR and HRMS spectra; [18F]MDL100907 (11) production data; radiometric and UV HPLC analysis of [18F]MDL100907 (11); and time–activity curves of regional brain uptake of [18F]MDL100907 (11) and [11C]MDL100907 (PDF)

Author Contributions

M.M.G. contributed to the study conception, study design, analysis, and interpretation of data, supervised the experiments, revised the manuscript, and approved the final version of the manuscript. L.N.C. contributed to design the chemical synthesis, performed the chemical and radiochemical labeling and interpretation of radiochemical labeling data, prepared the NHP time–activity curves, drafted the manuscript, including the chemical drawings contained in the manuscript, Figures, and Schemes, and revised the manuscript. R.V. contributed to the radiochemical labeling and interpretation of radiochemical labeling data. J.A.N. contributed to the NHP image processing and kinetic analysis of the NHP brain regional radioactivity measurements and created the NHP microPET images. M.S. was responsible for the NHP study design and the IACUC protocol approval.

This research was supported by the NIMH (R01-MH-Sanchez).

The authors declare no competing financial interest.

Supplementary Material

cn3c00382_si_001.pdf (3.6MB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

cn3c00382_si_001.pdf (3.6MB, pdf)

Data Availability Statement

The data will be available upon request.

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