Carbon‐11 labelling of MADAM in two different positions: a highly selective PET radioligand for the serotonin transporter

Abstract

Imaging by scintigraphy the serotonin transporter (5‐HTT) in the living human brain would be of great value in research on the pathophysiology and treatment of neuropsychiatric disorders such as depression. For that reason, and in order to obtain a selective radiotracer applicable to PET, we report here the carbon‐11 labelling of a selective 5‐HTT radioligand: N, N‐dimethyl‐2‐(2‐amino‐4‐methylphenylthio)benzylamine or MADAM in two different positions: [p‐11C‐methyl]MADAM and [N‐11C‐methyl]MADAM. The synthesis of Bu3Sn‐ADAM and N‐dimethyl‐MADAM is described. [p‐11C‐methyl]MADAM was obtained by a Stille coupling reaction between Bu3Sn‐ADAM and [11C]methyl iodide using palladium (0) as a catalyst without (Ia) or with copper chloride as a co‐catalyst (Ib). [N‐11C‐methyl]MADAM was obtained by an N‐methylation reaction between N‐demethyl‐MADAM and [11C]methyl iodide (II). The carbon‐11 incorporation yield in [p‐11C‐methyl]MADAM was 10–30% (Ia and Ib) and in [N‐11C‐methyl]MADAM was 75‐80% (II). The final product in each case was obtained in 30 min total synthesis time, including HPLC purification and with >99% radiochemical purity. Copyright © 2001 John Wiley & Sons, Ltd.

A PET study on regional coexpression of 5-HT1A receptors and 5-HTT in the human brain

“…Radiochemistry [ 11 C]MADAM was obtained by methylation of ADAM using [ 11 C]methyl iodide, as described previously (Hall et al 1997;Tarkiainen et al 2001). Between 286 and 318 MBq was injected intravenously.…”

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

“…These ligands include some of the most potent and selective compounds targeting the monoamine transporters, such as 2-(2-dimethylaminomethylphenylsulfanyl)-5-methylphenylamine (MADAM) and 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile (DASB) for SERT Tarkiainen et al, 2001;Meyer et al, 2004), 2␤-carbomethoxy-3␤-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane (FECNT) for DAT (Goodman et al, 2000), and 2-[(2-methoxyphenoxy)phenylmethyl]morpholine (MeNER) and methylreboxetine for NET (Ding et al, 2003;Schou et al, 2003Schou et al, , 2004Wilson et al, 2003) (Table 3).…”

Synthesis, radiolabeling and baboon SPECT imaging of 2β-carbomethoxy-3β-(3′-[123I]iodophenyl)tropane ([123I]YP256) as a serotonin transporter radiotracer

“…The PET tracer [ 11 C] (+)-McN-5652-Z has been used for several years 11 , even though its low target to background ratio limits its use to high density regions like the midbrain 12,13 . A fluorine-18 labeled analog [ 18 Based on the observations of Carroll 19 and Davies 20,21 that selectivity for 5-HTT was enhanced by unsaturated substituents on the phenyl ring and by N-demethylation (trends confirmed by preliminary results with 4′-substituted analogs 22,23 ), we synthesized a series of 3′-substituted tropane analogs and measured their binding affinity towards the three monoamine transporters. The potency (Ki, nM) of the compounds was evaluated by competition against radiolabeled ligands selective for 5-HTT, DAT, and NET in rat forebrain tissue and human cell membranes and binding selectivity was calculated as the inverse ratio of Ki values.…”