A two‐step one‐pot radiosynthesis of the potent dopamine D₂/D₃ agonist PET radioligand [¹¹C]MNPA

Abstract

Abstract(R)‐(−)‐2‐[11C]Methoxy‐N‐n‐propylnorapomorphine ([11C]MNPA ([11C]2)) is an agonist radioligand of interest for imaging D2/D3 receptors in vivo. Here we sought to develop an improved radiosynthesis of this radioligand. Reference 2 was synthesized in nine steps with an overall yield of about 5%, starting from codeine. Trimethylsilyldiazomethane proved to be a practical improvement in comparison to diazomethane in the penultimate methylation step. A protected precursor for radiolabeling ((R)‐(−)‐2‐hydroxy‐10,11‐acetonide‐N‐n‐propylnoraporphine, 4) was prepared from (R)‐(−)‐2‐hydroxy‐N‐n‐propylnorapomorphine (1) in 30% yield. [11C]2 was prepared from 4 via a two‐step one‐pot radiosynthesis. The first step, methylation of 4 with [11C]methyl triflate, occurred in quantitative radiochemical yield. The second step, deprotection of the catechol moiety with HCl and heat, yielded 60–90% of [11C]2 giving an overall incorporation yield from [11C]methyl triflate of 60–90%. In a typical run more than 1 GBq of [11C]2, was produced from carbon‐11 generated from a 10‐min proton irradiation (16 MeV; 35 µA) of nitrogen–hydrogen target gas. The radiochemical purity of [11C]2 was > 99% and specific radioactivity at the time of injection was 901±342 GBq/µmol (n=10). The total synthesis time was 35–38 min from the end of radionuclide production. The identity of [11C]2 was confirmed by comparing its LC‐MS/MS spectrum with those of reference 2 and (R)‐(−)‐10‐methoxy‐2,11‐dihydroxy‐N‐n‐propylnoraporphine. Copyright © 2009 John Wiley & Sons, Ltd.

D2 dopamine receptor internalization prolongs the decrease of radioligand binding after amphetamine: A PET study in a receptor internalization-deficient mouse model

“…The mean activity injected into mice was 5 ± 1 MBq, which was accompanied by 0.04 ± 0.02 nmol of carrier fallypride. [ 11 C]MNPA was prepared by 11 C-methylation of the precursor ( R )-2-hydroxy-10,11-acetonide-NPA using a two-step labeling method (Gao et al, 1990; Steiger et al, 2009). Chemical purity was >98%, and radiochemical purity was >95%.…”

“…Agonist radioligands for the dopamine D 2 receptor have recently been developed for in vivo PET imaging (Gao et al, 1990; Neumeyer et al, 1990; Steiger et al, 2009; Wilson et al, 2005). Based on in vitro binding studies, agonist PET radioligands are thought to bind in vivo preferentially to a high affinity state, whereas antagonists do not differentiate between high and low affinity states (Laruelle, 2000).…”

Dopamine β‐hydroxylase‐deficient mice have normal densities of D2 dopamine receptors in the high‐affinity state based on in vivo PET imaging and in vitro radioligand binding

“…[ 11 C]MNPA was prepared as previously described (Steiger et al,2009). The specific activity of [ 11 C]MNPA at the time of injection was 82 ± 24 GBq/μmol ( n = 8, syntheses).…”

18F-MCL-524, an 18F-Labeled Dopamine D2 and D3 Receptor Agonist Sensitive to Dopamine: A Preliminary PET Study

“…Direct fluorination of MCL-556 was followed by deprotection of the catechol moiety (supplemental information). 11 C-MNPA was prepared using previously described procedures (16). …”