11CO2 fixation: a renaissance in PET radiochemistry

Rotstein, Benjamin H.; Liang, Steven H.; Holland, Jason P.; Collier, Thomas Lee; Hooker, Jacob M.; Wilson, Alan A.; Vasdev, Neil

doi:10.1039/c3cc42236d

Cited by 94 publications

(119 citation statements)

References 84 publications

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“…Carbonyl group of the carbamate or urea moiety were radiolabeled via a one-pot [ 11 C]CO 2 fixation method (Scheme 1) used previously to radiolabel comparable compounds [22]. Bubbling cyclotron produced [ 11 C]CO 2 into a vial with appropriate piperidine or piperazine in the presence of a phosphazene base (BEMP, an efficient CO 2 capturing agent [24]) followed by the addition of POCl 3 resulted in the formation of a putative mixed anhydride [19].…”

Section: Resultsmentioning

confidence: 99%

“…Logically then, the carbamoyl group provides an ideal site to radiolabel these inhibitors, ensuring retention of the radioisotope by the enzyme. To attain this outcome, an automated, one pot carbon-11 labeled ( 11 C; β + ; t ½ = 20.4 min) CO 2 fixation method can be employed [22]. Using this technique, [ 11 C]carbamates [16,23,24], unsymmetrical [ 11 C]ureas [19,25,26], and [ 11 C]oxazolidines [27] have previously been prepared with sufficient yield, radiochemical purity and specific activity to complete preclinical and clinical evaluations.…”

Section: Introductionmentioning

confidence: 99%

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Radiosynthesis and ex vivo evaluation of [11C-carbonyl]carbamate- and urea-based monoacylglycerol lipase inhibitors

Hicks

Parkes

Tong

et al. 2014

Nuclear Medicine and Biology

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Radiosynthesis and ex vivo evaluation of [11C-carbonyl]carbamate- and urea-based monoacylglycerol lipase inhibitors

Hicks

Parkes

Tong

et al. 2014

Nuclear Medicine and Biology

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“…4 High [ 11 C]CO 2 trapping was obtained when BEMP was used however, no [ 11 C]1 was observed (see Supporting Information, Table SI1 and Table 1, entry 11).…”

Section: Letter Syn Lettmentioning

confidence: 72%

Synthesis of 11C-Labelled Symmetrical Ureas via the Rapid Incorporation of [11C]CO2 into Aliphatic and Aromatic Amines

Dheere

Bongarzone

Taddei

et al. 2015

Synlett

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An efficient method to radiolabel symmetrical [ 11 C]ureas using 1,8-diazabicycloundec-7-ene (DBU) and cyclotron-produced [ 11 C]CO 2 has been developed. [ 11 C]urea derivatives were obtained when aliphatic and aromatic amines were used with excellent radiochemical yields (RCYs) of over 70%. The mechanism of the reaction is proposed on the basis of control experiments. This simple and robust methodology provides a powerful tool to prepare 11 C-labelled ureas previously inaccessible by existing methods and enable their utilisation for in vivo molecular imaging applications.Positron emission tomography (PET) is a molecular imaging technique that is increasingly being used for diagnosis, biological research and drug development studies. 1 Short-lived carbon-11 (t 1/2 = 20.4 min) is one of the most commonly used radioisotopes for PET imaging. Carbon-11 ( 11 C) is produced by a cyclotron in the form of [ 11 C]CH 4 or [ 11 C]CO 2 by the 14 N(p,α) 11 C nuclear reaction. 1 From a synthetic perspective, both products are converted into more reactive secondary synthons such as [ 11 C]methyl iodide, [ 11 C]methyl tosylate for radiolabelling. 2 Although these secondary synthons are undoubtedly useful they require timeconsuming processing. Therefore, the development of methods to radiolabel compounds directly and efficiently with [ 11 C]CO 2 is of significant interest. 1-3 Due to low CO 2 reactivity, there are only a handful of radiosynthetic methods available to incorporate [ 11 C]CO 2 directly into target molecules of interest. 4 A challenge that needs to be addressed when developing synthetic methods with 11 C is that reactions are typically performed with reactants and supporting reagents in large excess compared to the 11 C synthons (typically [ 11 C]CO 2 is used on a nanomolar scale).We have recently developed a method to radiolabel asymmetric ureas with 11 C using [ 11 C]CO 2 directly from the cyclotron (Scheme 1). 5 However, when the method was applied to the synthesis of symmetrical ureas, low radiochemical yields (RCYs) were observed. Scheme 1 Synthesis of asymmetric [ 11 C]ureas using [ 11 C]CO 2We hereby report a new development of the previous methodology that allows the radiolabelling of symmetrical ureas in moderate to excellent RCYs using a Mitsunobu reaction.Initially, 11 C-radiolabelling of bis(4-methylpiperazin-1-yl)methanone ([ 11 C]1) was performed in two steps. Cyclotron-produced [ 11 C]CO 2 was bubbled in a solution containing N-methyl piperazine (18.3 μmol), 1,8-diazabicycloundec-7-ene (DBU, 0.8 μmol) in acetonitrile (MeCN, 300 μL) at room temperature (r.t.). The solution was heated at 50 °C and Mitsunobu reagents, di-tert-butyl azodicarboxylate (DBAD, 36.6 μmol) and tributylphosphine (PBu 3 , 36.6 μmol), dissolved in MeCN (100 μL) were added. The mixture was stirred for 4 minutes at 50 °C. 5 Following this procedure, [ 11 C]1 was obtained with a RCY of 31% (Table 1, entry 1). RCY was determined by radio-HPLC and defined as the amount of labelled [ 11 C]urea as a percentage of the cyclotron-produced [ ...

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“…Several PET radiotracers for FAAH have been reported, including anadamide analogues, 13 carbon-11 labeled PF-04457845 14 and a fluorine-18 labeled derivative, 15 [ 11 C]MK-3168, 16 a 11 C- methyl labeled URB597 analogue, 17 and related [ 11 C- carbonyl ]- O -arylcarbamates 18,19 prepared by 11 CO 2 -fixation in the presence of an organic base. 20 Among PET radiotracers for FAAH, only two have been reported in human studies, namely [ 11 C]MK-3168 21 and [ 11 C- carbonyl ]-6-hydroxy-[1,1′-biphenyl]-3-yl cyclohexylcarbamate ([ 11 C]CURB). 18,22 We are evaluating [ 11 C]CURB, which is an irreversible covalent inhibitor of FAAH.…”

Section: Introductionmentioning

confidence: 99%

PET Imaging of Fatty Acid Amide Hydrolase with [¹⁸F]DOPP in Nonhuman Primates

et al. 2014

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Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [11C]CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However, no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies. [18F]DOPP ([18F]3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate) has been identified as a promising 18F-labeled analogue based on rodent studies. The goal of this work is to evaluate [18F]DOPP in nonhuman primates to support its clinical translation. High specific activity [18F]DOPP (5–6 Ci·μmol–1) was administered intravenously (iv) to three baboons (2M/1F, 3–4 years old). The distribution and pharmacokinetics were quantified following a 2 h dynamic imaging session using a simultaneous PET/MR scanner. Pretreatment with the FAAH-selective inhibitor, URB597, was carried out at 200 or 300 μg/kg iv, 10 min prior to [18F]DOPP administration. Rapid arterial blood sampling for the first 3 min was followed by interval sampling with metabolite analysis to provide a parent radiotracer plasma input function that indicated ∼95% baseline metabolism at 60 min and a reduced rate of metabolism after pretreatment with URB597. Regional distribution data were analyzed with 1-, 2-, and 3-tissue compartment models (TCMs), with and without irreversible trapping since [18F]DOPP covalently links to the active site of FAAH. Consistent with previous findings for [11C]CURB, the 2TCM with irreversible binding was found to provide the best fit for modeling the data in all regions. The composite parameter λk3 was therefore used to evaluate whole brain (WB) and regional binding of [18F]DOPP. Pretreatment studies showed inhibition of λk3 across all brain regions (WB baseline: 0.112 mL/cm3/min; 300 μg/kg URB597: 0.058 mL/cm3/min), suggesting that [18F]DOPP binding is specific for FAAH, consistent with previous rodent data.

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11CO2 fixation: a renaissance in PET radiochemistry

Cited by 94 publications

References 84 publications

Radiosynthesis and ex vivo evaluation of [11C-carbonyl]carbamate- and urea-based monoacylglycerol lipase inhibitors

Radiosynthesis and ex vivo evaluation of [11C-carbonyl]carbamate- and urea-based monoacylglycerol lipase inhibitors

Synthesis of 11C-Labelled Symmetrical Ureas via the Rapid Incorporation of [11C]CO2 into Aliphatic and Aromatic Amines

PET Imaging of Fatty Acid Amide Hydrolase with [¹⁸F]DOPP in Nonhuman Primates

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11CO2 fixation: a renaissance in PET radiochemistry

Cited by 94 publications

References 84 publications

Radiosynthesis and ex vivo evaluation of [11C-carbonyl]carbamate- and urea-based monoacylglycerol lipase inhibitors

Radiosynthesis and ex vivo evaluation of [11C-carbonyl]carbamate- and urea-based monoacylglycerol lipase inhibitors

Synthesis of 11C-Labelled Symmetrical Ureas via the Rapid Incorporation of [11C]CO2 into Aliphatic and Aromatic Amines

PET Imaging of Fatty Acid Amide Hydrolase with [18F]DOPP in Nonhuman Primates

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PET Imaging of Fatty Acid Amide Hydrolase with [¹⁸F]DOPP in Nonhuman Primates