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Reductive Amination with [11C]Formaldehyde: a Versatile Approach to Radiomethylation of Amines

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Reductive Amination with [11C]Formaldehyde: a Versatile Approach to Radiomethylation of Amines International Journal of Organic Chemistry, 2012, 2, 202-223 http://dx.doi.org/10.4236/ijoc.2012.23030 Published Online September 2012 (http://www.SciRP.org/journal/ijoc) Reductive Amination with [11C]Formaldehyde: A Versatile Approach to Radiomethylation of Amines Chunying Wu1, Ruoshi Li1, Dorr Dearborn2, Yanming Wang1* 1Division of Radiopharmaceutical Science, Case Center for Imaging Research, Department of Radiology, Cleveland, USA 2Environmental Health, Case Western Reserve University, Cleveland, USA Email: *[email protected] Received February 16, 2012; revised March 24, 2012; accepted April 2, 2012 ABSTRACT Carbon-11 radiolabeled amines constitute a very important class of radioligands that are widely used for positron emis- 11 sion tomography (PET) imaging. Radiolabeling of amines is often achieved through radiomethylation using [ C]CH3I 11 or [ C]CH3OTf under basic conditions in a strictly anhydrous environment. Functional groups such as hydroxyl and carboxyl groups that are often present in the molecules are normally base sensitive and require protection and deprotec- tion, which substantially prolongs and complicates the radiolabeling process. Here we report a versatile approach to a series of C-11 radiolabeled amines prepared through reductive amination using [11C]formaldehyde. Using a variety of substrates bearing different functional groups, we demonstrate the general utility of this method. In contrast to conven- tional radiomethylation methods, the reductive amination using [11C]formaldehyde can be carried out in an aqueous environment relatively quickly without the need of protection of base-sensitive functional groups. Keywords: C-11 Formaldehyde; Radiomethylation; Reductive Amination; Positron Emission Tomography; Radiolabelling 1. Introduction probes must be labeled with positron-emitting radionu- clides such as carbon-11 or fluorine-18. The inherent Molecular imaging has become an indispensible tool in short half-lives of these positron emitters (20 min for biomedical research. To date, a variety of molecular im- C-11 and 110 min for F-18) make radiolabeling a very aging modalities have been established that complement timeconstrained process. In addition, these radionuclides each other in terms of sensitivity and resolution. Among need to be produced by a cyclotron not only in trace them, positron emission tomography (PET) and magnetic quantities but also in very limited forms. For example, resonance imaging (MRI) are widely used for clinical C-11 labelling is normally achieved through radiomethy- studies while optical imaging including multiphoton mi- lation using [11C]methyliodide [1] or [11C]methyltriflate croscopy, bioluminescence imaging, and fluorescent [2]. As a result, the chemical reactions with [11C]CH I or molecular tomography (FMT) are widely used for pre- 3 [11C]CH OTf must be carried out under very strict, often clinical studies. While each imaging modality is designed 3 air- and moisture-free conditions. Often times, a trace to detect different signals ranging from high-energy amount of water present either in the solvents or reagents gamma rays to low-energy radiofrequency, use of these reduces radiochemical yields significantly or even abol- imaging modalities largely depends on the availability of ishes the reactions. Other reactive functional groups such endogenous or exogenous molecular probes carrying the as hydroxyl or carboxyl groups present in the precursors required specific signals that can be readily detected at also need to be protected before radiolabeling and sub- the targets of interest. sequently deprotected after radiolabeling, which further Thus, significant efforts have been made to develop prolongs radiosynthesis time and complicates the purifi- molecular probes in line with advancements in mechani- cation process. cal design and optimization of imaging devices. While Radiomethylation has been the primary reaction used different sets of chemical and pharmacological properties to radiolabel alkylated amines, which constitute a very are required for different modalities, development of important class of PET radiotracers. Various amines have molecular probes for PET represents a unique challenge been identified as radiotracers for PET imaging of vari- in many aspects. This is largely due to the fact that PET ous molecular targets [3-18]. Given the fact that most *Corresponding author. amine radiotracers possess functional groups that are Copyright © 2012 SciRes. IJOC C. Y. WU ET AL. 203 either base-sensitive or can be readily methylated, C-11 action for C-11 radiolabeling of amines, we used a series radiolabeling of those functionalized amines must un- of amine precursors bearing functional groups. Func- dergo extensive protection and deprotection processes tional groups such as hydroxyl or carboxyl are reactive 11 11 before they are subjected to radiomethylation with toward [ C]CH3I or [ C]CH3OTf under conventional 11 11 [ C]CH3I or [ C]CH3OTf under basic conditions. In radiolabeling conditions and ought to be protected first. order to skip the protection/deprotection steps, efforts Through reductive amination with [11C]formaldehyde, have been made to radiolabel certain functionalized the aniline derivatives bearing hydroxyl group (1a, 2a, 3a) amines based on different reactivity toward C-11 methy- were directly radiomethylated in good radiochemical 11 lating reagents. For example, for the radiolabeling of PIB, yield. In contrast to radiomethylation with [ C]CH3I or 11 direct radiomethylation was achieved in an HPLC loop [ C]CH3OTf, which must be carried out in strictly anhy- 11 filled with unprotected precursor using [ C]CH3OTf [19]. drous solvents, the reductive animation can be performed 11 This is because [ C]CH3OTf reacts with amino groups in aqueous solvent like PBS. For compounds that are not faster than hydroxyl groups. However, this method is water-soluble, they can be first dissolved in DMF and applicable only to certain functionalized amines and is diluted with PBS. Thus, the whole process does not re- limited to small-production. quire use of any anhydrous solvents or reagents. The In addition to direct methylation, another important reductive amination was fast and could be completed approach to synthesizing alkylated amines is reductive within 5 min. After the reaction, the product can be di- amination, which has long been used in organic synthesis. rectly purified by HPLC with >95% purity. The geome- In this reaction, amines are first carbonylated with alde- try of the hydroxyl group relative to the amino group did hydes, ketones, or carboxylates to form imines followed not exert significant impact on the radiochemical yield by subsequent reduction. To apply this reaction to radio- (see Purification for compounds 1b - 7b) [24]. Compared labeling, C-11-radiolabeled aldehyes, ketones and car- to radiomethylation of 2a and 3a, radiomethylation of 1a boxylic acids need to be prepared. In 2000, Perrio-Huard gave a relatively lower yield. This may be due to the fact 11 and coworkers radiolabeled [ C]amines through reduc- that a cyclic hydrogen bond exists between the amino 11 tive amination using [ C]magnesium halide carboxylates, group and the hydroxyl group in the para-position, deac- 11 11 which was converted directly from [ C]CO2. In 2003, tivating the amino group toward [ C]formaldehyde. 11 Van der Meij and coworkers synthesized [ C]acetone The striking versatility of reductive methylation with and used it for reductive amination for radiolabeling of [11C]formaldehyde was also demonstrated by radiome- 1-phenyl-piperazine [20]. In the meantime, Langstrom thylation of amines bearing a free carboxyl group (4a). and coworkers established a general approach to With no protection of the carboxyl group, the amino 11 [ C]ketones through Suzuki coupling [21]. Subsequently, group can be readily radiomethylated. While conven- 11 11 various [ C]ketones were transformed to [ C]amines 11 11 tional radiomethylation using [ C]CH3I or [ C]CH3OTf through reductive amination. often requires refluxing at temperature over 120˚C, the Recently, Hooker et al. has reported a simple and di- reductive amination reaction can be run at relatively low rect method for the preparation of C-11 formaldehyde 11 temperatures. The radiochemical yield was significantly ([ C]HCHO, see general procedure for synthesis) [22]. improved when the reaction temperature was elevated to This opens the way to radiolabel methylated amines 90˚C. Interestingly, adding aqueous PBS to the reaction through reductive amination. The advantage of reductive media dramatically increases the radiochemical yield. amination over conventional radiomethylation is that the At 90˚C, the radiochemical yield was increased ca. 5-fold reaction can be carried out in aqueous solution. So the when the reaction was run in DMF-PBS (1:3) versus in reagents are not necessarily anhydrous. In addition, DMF alone. base-sensitive functional groups present in the molecule Radiomethylation using [11C]formaldehyde was found do not interfere with the reaction, which eliminates pro- to be selective for primary amines. The reaction selectiv- tection /deprotection steps. In this study, we report C-11 ity for primary amino group was demonstrated in the labelling of a series of amines through reductive amina- reductive methylation reaction of serotonin (5a), a widely tion using C-11 formaldehyde in order to demonstrate the studied neurotransmitter. Previous radiolabeling of sero- general utility of this method. 11 11 tonin with [ C]CH3I
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