Efficient synthesis of enantiomerically pure thioester precursors of [11C]McN-5652 from racemic McN-5652

Zessin, J.; Gucker, P.; Ametamey, Simon M.; Steinbach, J.; Brust, Peter; Vollenweider, F.X.; Johannsen, B.; Schubiger, P. A.

doi:10.1002/(sici)1099-1344(19991230)42:13<1301::aid-jlcr298>3.0.co;2-2

Cited by 12 publications

(7 citation statements)

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“…The parent compound, McN-5652, was prepared starting from 2-phenylpyrrolidine and 4-methylthiomandelic acid in a five-step synthesis, as reported previously (Maryanoff et al, 1987; Sorgi et al, 1990). Enantiomerically pure (+)McN-5652 was obtained by crystallization of McN-5652 with (−)-di- p -toluyltartaric acid (Zessin et al, 1999). The transformation of (+)McN-5652 to the corresponding thioester precursor was achieved by S -demethylation with sodium amide at low temperatures (−78°C) followed by conversion of the intermediate thiol with acetyl chloride (Zessin et al, 1999).…”

Section: Methodsmentioning

confidence: 99%

Evaluation of Serotonergic Transporters using PET and [¹¹C](+)McN-5652: Assessment of Methods

Buck

Gucker

Schönbächler

et al. 2000

J Cereb Blood Flow Metab

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[11C](+)McN-5652 is an established positron emission tomography tracer used to assess serotonergic transporter density. Several methods have been used to analyze [11C](+)McN-5652 data; however, no evaluation of candidate methods has been published in detail yet. In this study, compartmental modeling using a one-tissue compartment model (K1, k2"), a two-tissue compartment model (K1 to k4), and a noncompartmental method that relies on a reference region devoid of specific binding sites were assessed. Because of its low density of serotonergic transporters, white matter was chosen as reference. Parameters related to transporter density were the total distribution volume DV" (= K1/k2", one tissue compartment), DVtot, (=K1/k1' (1 + k3/k4), two tissue compartments), and Rv (= k3'/k4, noncompartmental method). The DV", DVtot, and Rv values extended over a similar range and reflected the known pattern of serotonergic transporters. However, all parameters related to transporter density were markedly confounded by nonspecific binding. With regard to K1, the one-tissue compartment model yielded markedly lower values, which were, however, more stable. The minimal study duration needed to determine stable values for the distribution volume was approximately 60 minutes. The choice of the method to analyze [11C](+)McN-5652 data depends on the situation. Parametric maps of Rv are useful if no information on K1 is needed. If compartmental modeling is chosen, both the one- and the two-tissue compartment models have advantages. The one-tissue compartment model underestimates K1 but yields more robust values. The distribution volumes calculated with both models contain a similar amount of information. None of the parameters reflected serotonergic transporter density in a true quantitative manner, as all were confounded by nonspecific binding.

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Section: Methodsmentioning

confidence: 99%

Evaluation of Serotonergic Transporters using PET and [¹¹C](+)McN-5652: Assessment of Methods

Buck

Gucker

Schönbächler

et al. 2000

J Cereb Blood Flow Metab

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“…1) was carried out as described recently by Zessin et al (2001). Normethyl(ϩ)McN5652 1 was prepared immediately before radiosynthesis from the enantiomerically pure thioester analog of (ϩ)McN5652, the synthesis of which is described by Zessin et al (1999). High specific radioactivity [ 18 F]bromofluoromethane, the fluoromethylation reagent, was synthesized according to the procedures previously described by Eskola et al (1999) and Bergman et al (2001).…”

Section: Radiosynthesis Of [ 18 F]fme-mcnmentioning

confidence: 99%

“…However, the kinetics of [ 11 C](ϩ)McN5652 in the human brain is slow compared to the short half-life of 20.4 min for carbon-11. To obtain a tracer with longer physical half-life, Suehiro et al (1996) Recently, Zessin et al (1999) developed an efficient synthesis method for enantiomerically pure thioester precursors from racemic McN5652. From this, Zessin et al (2001) synthesized the [ 18 F]fluoromethyl analog of (ϩ)-McN5652 ([ 18 F]FMe-McN) using the methods described by Eskola et al (1999) and Bergman et al (2001).…”

Section: Introductionmentioning

confidence: 99%

S‐[¹⁸F]fluoromethyl‐(+)‐McN5652, a PET tracer for the serotonin transporter: Evaluation in rats

Marjamäki

Zessin

Eskola

et al. 2002

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The [(18)F]fluoromethyl analog of (+)-McN5652 ([(18)F]FMe-McN) for imaging serotonin transporter (SERT) with positron emission tomography (PET) has recently been synthesized. We describe here the biological evaluation of [(18)F]FMe-McN in rats. Biodistribution studies of [(18)F]FMe-McN in rat brain ex vivo after an intravenous injection showed a high accumulation of radioactivity in the regions rich in SERT, such as raphe nuclei, hypothalamus, thalamus, substantia nigra, locus coeruleus, and amygdala. Region-to-cerebellum ratios reached a maximum value of 9 in raphe nuclei within 3.5 h after administration. The specificity and selectivity of [(18)F]FMe-McN binding to SERT was studied by preinjecting blocking doses of serotonin, norepinephrine, and dopamine transporter inhibitors. Fluoxetine, a specific inhibitor for SERT, decreased the specific binding of [(18)F]FMe-McN in raphe nuclei by 91 +/- 4%; in other regions rich in SERT, similar results were obtained. GBR12909 and nisoxetine, selective inhibitors for dopamine transporter (DAT) and norepinephrine transporter (NET), respectively, showed no significant effects on the uptake of [(18)F]FMe-McN. Our studies show that [(18)F]FMe-McN has a clear potential as a tracer for studies with PET of SERT function in humans.

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“…The present study was performed to investigate the in vivo kinetics of [ (Zessin et al, 1999(Zessin et al, , 2001. Briefly, the thioester precursors were prepared from enantiomerically pure (+)-McN5652 or (À)-McN5652 by Sdemethylation with sodium amide, followed by conversion of the thiols with acetyl chloride.…”

Section: Introductionmentioning

confidence: 99%

In vivo Measurement of the Serotonin Transporter with (S)-([18F]fluoromethyl)-(+)-McN5652

Brust¹,

Hinz

Kuwabara

et al. 2003

Neuropsychopharmacol

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The radiolabeled serotonin transporter (SERT) ligand [ 11 C](+)-McN5652 has recently been used in clinical positron emission tomography (PET) studies for SERT imaging. However, this radioligand offers disadvantages in routine clinical settings because of its short radioisotope half-life (eg PET facilities within hospitals without a cyclotron need to acquire such radioligands from distant cyclotron units for clinical use).is an analogue which has been synthesized newly, and has a significantly longer radioisotope half-life. In the porcine brain, it demonstrates the same characteristic distribution pattern of serotonin-uptake sites like the 11 C-labeled congener with the highest binding in the midbrain and thalamus and the lowest in the cerebellum and occipital cortex. It shows a 30% higher blood-brain transfer and a slower peripheral metabolism than

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Efficient synthesis of enantiomerically pure thioester precursors of [11C]McN-5652 from racemic McN-5652

Cited by 12 publications

References 0 publications

Evaluation of Serotonergic Transporters using PET and [¹¹C](+)McN-5652: Assessment of Methods

Evaluation of Serotonergic Transporters using PET and [¹¹C](+)McN-5652: Assessment of Methods

S‐[¹⁸F]fluoromethyl‐(+)‐McN5652, a PET tracer for the serotonin transporter: Evaluation in rats

In vivo Measurement of the Serotonin Transporter with (S)-([18F]fluoromethyl)-(+)-McN5652

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Efficient synthesis of enantiomerically pure thioester precursors of [11C]McN-5652 from racemic McN-5652

Cited by 12 publications

References 0 publications

Evaluation of Serotonergic Transporters using PET and [11C](+)McN-5652: Assessment of Methods

Evaluation of Serotonergic Transporters using PET and [11C](+)McN-5652: Assessment of Methods

S‐[18F]fluoromethyl‐(+)‐McN5652, a PET tracer for the serotonin transporter: Evaluation in rats

In vivo Measurement of the Serotonin Transporter with (S)-([18F]fluoromethyl)-(+)-McN5652

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Evaluation of Serotonergic Transporters using PET and [¹¹C](+)McN-5652: Assessment of Methods

Evaluation of Serotonergic Transporters using PET and [¹¹C](+)McN-5652: Assessment of Methods

S‐[¹⁸F]fluoromethyl‐(+)‐McN5652, a PET tracer for the serotonin transporter: Evaluation in rats