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