Radiosynthesis of (S)‐5‐methoxymethyl‐3‐[6‐(4,4,4‐trifluorobutoxy)benzo[d]isoxazol‐3‐yl] oxazolidin‐2‐[¹¹C]one ([¹¹C]SL25.1188), a novel radioligand for imaging monoamine oxidase‐B with PET

Abstract

Radiosynthesis of (S)-5-methoxymethyl-3- [6-(4,4,4-trifluorobutoxy) Within a novel series of 2-oxazolidinones developed in the past by Sanofi-Synthé labo, SL25.1188 ((S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)benzo [d]isoxazol-3-yl]oxazolidin-2-one), a compound that inhibits selectively and competitively MAO-B in human and rat brain (Ki values of 2.9 and 8.5 nM for MAO-B, respectively, and ED 50 (rat) : 0.6 mg/kg p.o.), was considered an appropriate candidate for imaging this enzyme with positron emission tomography. SL25.1188 was labelled with carbon-11 (T 1/2 : 20.38 min) in one chemical step using the following process: (i) reaction of [ 11 C]phosgene with the corresponding ring-opened precursor (1.2-2.5 mg) at 1001C for 2 min in dichloromethane (0.5 mL) followed by (ii) concentration to dryness of the reaction mixture and finally (iii) semi-preparative HPLC purification on a Waters Symmetry s C18. A total of 300-500 MBq of [ 11 C]SL25.1188 (> 95% chemically and radiochemically pure) could be obtained within 30-32 min (Sep-pak-based formulation included) with specific radioactivities ranging from 50 to 70 GBq/lmol (3.5-7% decay-corrected radiochemical yield, based on starting [11 C]CH 4 ).Keywords: SL25.1188; carbon-11; phosgene; MAO-B IntroductionMonoamine oxidase (MAO) is an integral protein of outer mitochondrial membranes and occurs in neuronal and nonneuronal cells in the brain and in peripheral organs. 1,2 Two isoforms, termed MAO-A and MAO-B, have been described, each consisting of two subunits 3,4 coded by different genes and with molecular weights of about 59 700 and 58 800 D, 5 respectively. MAOs catalyse the oxidative deamination of both endogenous and exogenous amines 6 with its two isoforms differing in substrate specificity and inhibitor sensitivity. MAO-A preferentially deaminates 5-hydroxytryptamine (serotonin), norepinephrine and epinephrine and is selectively inactivated by low concentrations of clorgyline.7 MAO-B preferentially deaminates phenethylamine and benzylamine and is selectively inhibited by low concentrations of deprenyl.8 Dopamine and tyramine are metabolized by both forms.9-11 Nevertheless, this specificity is relative and the deamination of a given substrate by MAO-A or MAO-B depends not only on the substrate itself but also on the relative concentration of each form of MAO. Histochemical, immunohistochemical and autoradiographic studies have revealed that the two isoforms of MAO also have a distinct regional brain distribution, with MAO-A found primarily in catecholaminergic neurones and MAO-B localized in serotoninergic neurones and glial cells.Fluctuations in functional MAO activity, directly impacting the concentration of neurotransmitters as well as many xenobiotics, have been associated with human diseases such as Parkinson's disease, depression and certain psychiatric disorders, [12][13][14][15][16] reinforcing the potential role of positron emission tomography (PET) to the in vivo and non-invasive study of these enzymes. A few compounds have already been proposed as...

11CO bonds made easily for positron emission tomography radiopharmaceuticals

“…The reversible monoamine oxidase B (MAO-B) PET radiotracer SL25.1188 was developed using [ 11 C]COCl 2 , but this method presents technical challenges for widespread use. 79 In a bid to improve the accessibility and the isolated yield of [ 11 C]SL25.1188, the amino alcohol precursor was deployed in [ 11 C]CO 2 -fixation and enabled translation for human PET imaging in clinical research studies (Fig. 3).…”

“…124 Indeed, [ 11 C- methyl ]befloxatone is currently used in human imaging research. 125 As discussed earlier, reversible oxazolidinone MAO-B radioligands [ 11 C]SBox-13 and [ 11 C]SL25.1188 were originally developed using [ 11 C]COCl 2 , 79,126,127 but improvements in the synthesis of the latter compound using [ 11 C]CO 2 -fixation have enabled human translation (Fig. 3).…”

11CO2 fixation: a renaissance in PET radiochemistry

“…The original synthesis employed [ 11 C]phosgene, and suffered from a low 3.5 – 7% decay-corrected RCY with 50 – 70 GBq·μmol -1 specific activity after a 30 – 32 minutes. 78 We recently reported the application of the amino-alcohol precursor for [ 11 C]CO 2 fixation followed by dehydration and intramolecular cyclization to improve the radiosynthesis. 79 After optimization of the fixation base, dehydrating agent, and component concentrations, conditions were developed to perform the labelling at ambient temperature using BEMP and POCl 3 .…”

Radiochemistry devoted to the production of monoamine oxidase (MAO‐A and MAO‐B) ligands for brain imaging with positron emission tomography

“…Figure shows the direct labeling of SL25.1188 with [ 11 C]phosgene according to the method described by Bramoullé et al . in 2008 . [ 11 C]Phosgene was trapped at room temperature for 1–2 min in dichloromethane containing the ring‐opened precursor (( R )‐1‐ methoxy‐3‐[[4‐[(3 R )‐4,4,4‐trifluoro‐3‐hydroxybutoxy]phenyl]amino]‐2‐propanol).…”