Synthesis of ([11C]carbonyl)raclopride and a comparison with ([11C]methyl)raclopride in a monkey PET study

https://doi.org/10.1016/j.nucmedbio.2015.07.003Get rights and content

Abstract

Introduction

The selective dopamine D2 receptor antagonist raclopride is usually labeled with carbon-11 using [11C]methyl iodide or [11C]methyl triflate for use in the quantification of dopamine D2 receptors in human brain. The aim of this work was to label raclopride at the carbonyl position using [11C]carbon monoxide chemistry and to compare ([11C]carbonyl)raclopride with ([11C]methyl)raclopride in non-human primate (NHP) using PET with regard to quantitative outcome measurement, metabolism of the labeled tracers and protein binding.

Methods

Palladium-mediated carbonylation using [11C]carbon monoxide, 4,6-dichloro-2-iodo-3-methoxyphenol and (S)-(-)-2-aminomethyl-1-ethylpyrrolidine was applied in the synthesis of ([11C]carbonyl)raclopride. The reaction was performed at atmospheric pressure using xantphos as supporting phosphine ligand and palladium (π-cinnamyl) chloride dimer as the palladium source. ([11C]Methyl)raclopride was prepared by a previously published method. In the PET study, two female cynomolgus monkeys were used under gas anesthesia of sevoflurane. A dynamic PET measurement was performed for 63 min with an HRRT PET camera after intravenous injection of ([11C]carbonyl)raclopride and ([11C]methyl)raclopride, respectively, during the same day. The order of injection of the two PET radioligands was changed between the two monkeys. The venous blood sample for measurement of protein binding was taken 3 min prior to the PET scan. Binding potential (BPND) of the putamen and caudate was calculated with SRTM using the cerebellum as a reference region.

Results

The target compound ([11C]carbonyl)raclopride was obtained with 50 ± 5% decay corrected radiochemical yield and 95% radiochemical purity. The trapping efficiency (TE) of [11C]carbon monoxide was 65 ± 5% and the specific radioactivity of the final product was 34 ± 1 GBq/μmol after a 50 min of synthesis time. The radiochemical yield of ([11C]methyl)raclopride was in the same range as published previously i. e. 50–60% and specific radioactivity of those two batches which were used in the present PET study were 192 GBq/μmol and 638 GBq/μmol respectively after a synthesis time of 32 min. In monkey PET studies, the percentage difference of BPND in putamen was < 3% and that in caudate was < 9% for the two radioligands. The plasma protein binding was 86.2 ± 0.3% and 85.7 ± 0.6% for ([11C]carbonyl)raclopride and ([11C]methyl)raclopride, respectively. The radiometabolite pattern was similar for both radioligands.

Conclusion

Raclopride was 11C-labeled at the carbonyl position using a palladium-mediated [11C]carbonylation reaction. A comparison between ([11C]carbonyl)raclopride and ([11C]methyl)raclopride with regard to quantitative PET outcome measurements, metabolism of radioligands and protein binding in monkey was performed. The monkey PET study with ([11C]carbonyl)raclopride showed similar results as for ([11C]methyl)raclopride. The PET studies were performed on 2 subjects.

Introduction

Positron emission tomography (PET) is non-invasive and one of the most sensitive molecular imaging techniques. In clinical diagnostic imaging, PET has become a useful tool in complement to CT and MRI. Moreover, PET can play an important role in pharmaceutical research and drug development [1], [2]. The successful use of PET in clinical diagnosis and medical, biomedical and pharmaceutical research depends on the availability of suitable radiolabeling methods. Carbon-11 is an ideal radioisotope in PET and the most commonly used method for the synthesis of 11C-labeled compounds is methylation using [11C]methyl iodide [3] or [11C]methyl triflate [4], [5]. However, the interest for [11C]carbon monoxide (11CO) chemistry, which offers the possibility to label the tracer molecules at a carbonyl position, has increased notably in recent years [6], [7], [8]. A carbonyl group has different metabolic stability in the biological system compared to a methyl group on an alcohol, phenol, amine or carboxylate and in some cases the 11C-labeling at a carbonyl position makes the molecule a preferable PET radioligand [9], [10]. Moreover, [11C]carbonylation offers a possibility to apply a combinatorial concept to PET tracer development since a wide variety of electrophiles and nucleophiles can be tested with a single optimization of reaction conditions [11], [12]. The combinatorial approach could be applied to make a small library of the analogs of an interesting target compound for identifying the best analog of the compound. In case of [11C]raclopride, it is possible to make a number of 11C-labeled analogs of that compound containing phenyl group with other substituent than methoxy which is not possible in case of the [11C]methylation approach. The most commonly used method for the synthesis of [11C]raclopride is O-methylation of the phenolic hydroxyl group using methyl iodide [13] or methyl triflate [14].

Raclopride is a moderately high affinity (1–2 nM) selective antagonist for the dopamine-D2 receptor [15]. 11C-Labeled raclopride was developed as a useful PET tracer for characterizing dopamine-D2 receptors in human brain [16], [17]. [11C]Raclopride was also used to determine the dopamine-D2 receptor occupancy in patients treated with neuroleptic drugs [18], [19]. All those PET studies were performed using ([11C]methyl)raclopride. Although a paper has recently been published about the synthesis of ([11C]carbonyl)raclopride [20], to the best of our knowledge, no PET studies were performed using ([11C]carbonyl)raclopride so far. The objective of the present work was to prepare ([11C]carbonyl)raclopride using [11C]carbon monoxide chemistry and to perform a comparison between ([11C]carbonyl)raclopride and ([11C]methyl)raclopride in non-human primate (NHP) using PET with regard to quantitative outcome measurements, metabolism of radioligands and protein binding.

Section snippets

General

All chemicals and solvents were purchased from Sigma-Aldrich (Stockholm, Sweden) and used without further purification. The precursor for ([11C]carbonyl)raclopride was custom synthesized by SyTracks A/S (Copenhagen, Denmark). The authentic reference of ([11C]carbonyl)raclopride was purchased from PharmaSynth AS (Tartu, Estonia). Solid phase extraction (SPE) cartridges were purchased from Waters Sverige AB (Stockholm, Sweden). Sterile phosphate buffered saline (PBS), sterile water and sterile

Radiochemistry

([11C]Carbonyl)raclopride was prepared by [11C]aminocarbonylation of 4,6-dichloro-2-iodo-3-methoxyphenol (1) with (S)-(-)-2-aminomethyl-1-ethylpyrrolidine (2) using Pd2(π-cinnamyl)Cl2-xantphos as catalyst in anhydrous THF (Scheme 1).

The trapping and incorporation of 11CO was carried out at ambient pressure following a protocol published previously [26]. [11C]Carbonyl labeled raclopride (3) was obtained in a reproducible radiochemical yield (RCY) of 50 ± 5% (calculated from the total radioactivity

Conclusion

Raclopride was labeled with 11C at the carbonyl position using a one pot and one step palladium-mediated [11C]aminocarbonylation reaction and the resulting product was used in a monkey PET study. The PET-comparison between ([11C]carbonyl)raclopride and ([11C]methyl)raclopride with regard to quantitative outcome measurements, formation of radiometabolites and protein binding demonstrated similar results in all aspects. The PET studies were performed on 2 subjects.

Acknowledgment

The authors would like to thank the members of the PET group involved in these experiments at Karolinska Institutet. This work was supported by the EU project Mindview, project no. K831218133.

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