Radiosynthesis of 3‐[18F]fluoropropyl and 4‐[18F]fluorobenzyl triarylphosphonium ions

3‐[¹⁸F]Fluoropropyl‐, 4‐[¹⁸F]fluorobenzyl‐triphenylphosphonium and 4‐[¹⁸F]fluorobenzyltris‐4‐dimethylaminophenylphosphonium cations were synthesized in multi‐step reactions from no carrier added (nca) [¹⁸F]fluoride. The time for synthesis, purification, and formulation was 56, 82, and 79 min with an average radiochemical yield of 12, 6 and 15%, respectively (not corrected for decay). The average specific radioactivity for the three radiolabeled compounds was 14.9 GB q/µmole (403 mCi/µmole) at end of synthesis (EOS). Copyright © 2004 John Wiley & Sons, Ltd.     

Radiosynthesis of the α4β2 nicotinic acetylcholine receptor ligand: 5‐((1‐[11C]‐methyl‐2‐(S)‐pyrrolidinyl)methoxy)‐2‐chloro‐3‐((E)‐2‐(2‐fluoropyridin‐4‐yl)vinyl)pyridine

5‐((1‐[¹¹C]‐methyl‐2‐(S)‐pyrrolidinyl)methoxy)‐2‐chloro‐3‐((E)‐2‐(2‐fluoropyridin‐4‐yl)‐vinyl)pyridine ([¹¹C]‐FPVC) was synthesized from [¹¹C]‐methyl iodide and the corresponding normethyl precursor. The average time of synthesis, purification, and formulation was 42 min with an average non‐decay‐corrected radiochemical yield of 19%. The average specific radioactivity was 359 GBq/µmol (9691 mCi/µmole) at end of synthesis (EOS). Copyright © 2006 John Wiley & Sons, Ltd.     

New method for routine production of L‐[methyl‐11C]methionine: in loop synthesis

A fast, clean and reproducible method for the manufacture of the radiotracer L‐[methyl‐¹¹C]methionine is reported. The reaction at room temperature of the non‐radioactive precursor L‐homocysteine (1 mg solution in ethanol/water 50/50) with [¹¹C]CH₃I in an HPLC loop led to the formation of the desired radiotracer with a high radiochemical yield (38.4±4.1% end of synthesis) in a short production time (12 min). Radiochemical purity of the final radiotracer was 99.9±0.05%. Specific activities in the range 11–45 GBq/µmol were obtained. The presence of the undesired enantiomer (D‐[methyl‐¹¹C]methionine) was not detected in any of the cases. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of [11C]gefitinib for imaging epidermal growth factor receptor tyrosine kinase with positron emission tomography

We have synthesized N‐(3‐chloro‐4‐fluorophenyl)‐7‐[¹¹C]methoxy‐6‐[3‐(morpholin‐4‐yl)propoxy]quinazolin‐4‐amine, [¹¹C]gefitinib ([¹¹C]Iressa), a high affinity (IC₅₀ = 2 nM) inhibitor of the epidermal growth factor receptor tyrosine kinase (EGFR‐TK), in solution and in a semi‐automated stainless loop methylation system using [¹¹C]methyl triflate. The trapping efficiency for [¹¹C]methyl triflate in solution was higher than in the solvent film generated in the loop system, thus the overall radiochemical yield was considerably higher for the synthesis in solution. The average radiochemical yield for the solution chemistry was 15% with an average specific radioactivity of approximately 9000 mCi/µmole at EOS in one step from its corresponding desmethyl phenol precursor. Copyright © 2006 John Wiley & Sons, Ltd.     

Radiosynthesis and validation of [Carboxy‐11C]4‐Aminobenzoic acid ([11C]PABA), a PET radiotracer for imaging bacterial infections

In this practitioner protocol, the radiochemical synthesis of [¹¹C] PABA is described in detail, and a quality control summary of three validation productions is presented. The results indicate that the radiotracer product can be produced in good radiochemical yield (14% at end‐of‐synthesis (EOS)) at high specific activity (molar activity 11 Ci/μmole EOS; 407 GBq/μmole) and high chemical and radiochemical purity as a sterile, pyrogen‐free solution suitable for injection conforming to current Good Manufacturing Practice (cGMP) requirements.     

Synthesis of a [18F]fluoroethyltriazolylthymidine radiotracer from [18F]2‐fluoroethyl azide and 5‐ethynyl‐2′‐deoxyuridine

An improved synthesis for a fluoroethyltriazolylthymidine analog has been developed by employing the copper(I)‐catalyzed click chemistry reaction between 5‐ethynyl‐2′‐deoxyuridine (EDU) and [^19/18F]2‐fluoroethyl azide. When compared with the previously reported protocol the radiochemical yield has been increased from 3 to 32.5 ± 2.5%. The synthesis time was 130 min and the specific activity ranged from 70.3 to 129.5 GBq/µmol. The tracer was found to be stable in human plasma and was subsequently evaluated in an A431 tumor model in BALB/c nude mice. Dynamic image acquisition using the Mosaic small animal PET scanner showed that the tumor to muscle ratio reached a maximum value of 2.1 from 22 min postinjection. These results indicate, that the fluoroethyltriazolylthymidine synthesized can be a promising radiotracer for tumor cell proliferation and thus become an important tool for treatment evaluation in oncology. Copyright © 2011 John Wiley & Sons, Ltd.     

Microwave‐assisted radiosynthesis of [18F]ASEM,a radiolabeled α7‐nicotinic acetylcholine receptor antagonist

An improvement of the original radiochemical synthesis of [¹⁸F]ASEM, an α7‐nicotinic acetylcholinergic receptor radioligand, is reported. The new procedure utilizes microwave‐assisted radiofluorination. In addition, a new preparative HPLC method was developed to eliminate a chemical impurity in the final product. Quality control procedures were also enhanced to improve detection of product with enhanced resolution of potential impurities. [¹⁸F]ASEM was produced in 20.1 ± 8.9% non‐decay corrected (NDC) yield with an average synthesis time of 57 min and an average specific radioactivity of 856 ± 332 GBq/µmol (23 ± 9 Ci/µmol).     

A microwave radiosynthesis of the 4‐[18F]‐fluorobenzyltriphenylphosphonium ion

The 4‐[¹⁸F]‐fluorobenzyltriphenylphosphonium cation was synthesized by a series of microwave reactions from no carrier added [¹⁸F]‐fluoride. The microwave procedure reduced the quantity of reagents used and synthesis time when compared with the original synthesis. In addition, problematic solid phase extraction, sodium borohydride reduction by column and inconsistent yields with excessive precipitate formation during the bromination step were eliminated. The 4‐[¹⁸F]‐fluorobenzyltriphenylphosphonium cation was produced radiochemically pure in 8.3% yield with a specific radioactivity of 534.5 ± 371.4 GBq/µmole at end of synthesis.     

Synthesis of a mGluR5 antagonist using [11C]copper(I) cyanide

5‐(2‐Phenylethynyl)pyridine‐3‐[¹¹C]carbonitrile ([¹¹C]LY2232645), a metabotropic glutamate 5 receptor (mGluR5) antagonist, was synthesized by a no‐carrier‐added nucleophilic halogen displacement with [¹¹C]copper(I) cyanide. The average radiochemical yield was 2.5%, and the average specific activity was 1365 mCi/µmol at end‐of‐synthesis. The total time of synthesis, purification, and formulation was 26 min. Copyright © 2006 John Wiley & Sons, Ltd.     

Radiosynthesis and validation of [5‐cyano‐N‐(4‐(4‐[11C]methylpiperazin‐1‐yl)‐2‐(piperidin‐1‐yl)phenyl) furan‐2‐carboxamide] ([11C]CPPC), a PET radiotracer for imaging CSF1R,a microglia‐specific marker

In this practitioner protocol, the radiochemical synthesis of [¹¹C]CPPC is described in detail, and a quality control summary of three validation productions is presented. The results indicate that the radiotracer product can be produced in good radiochemical yield (> 60 mCi (2.22 GBq) at end‐of‐synthesis (EOS)), at high specific activity (molar activity > 11,435 mCi/μmole (423 GBq/μmole) at EOS) and high chemical and radiochemical purity. The entire production conforms to current Good Manufacturing Practice (cGMP) requirements. The final product is formulated as a sterile, pyrogen‐free solution suitable for human injection.     

An improved synthesis of the radiolabeled prostate‐specific membrane antigen inhibitor, [18F]DCFPyL

The radiosynthesis of [¹⁸F]DCFPyL on 2 distinct automated platforms with full regulatory compliant quality control specifications is described. The radiotracer synthesis was performed on a custom‐made radiofluorination module and the Sofie Biosciences ELIXYS. The radiofluorination module synthesis was accomplished in an average of 66 minutes from end of bombardment with an average specific activity at end of synthesis (EOS) of 4.4 TBq/μmol (120 Ci/μmol) and an average radiochemical yield of 30.9% at EOS. The ELIXYS synthesis was completed in an average of 87 minutes with an average specific activity of 2.2 TBq/μmol (59.3 Ci/μmol) and an average radiochemical yield of 19% at EOS. Both synthesis modules produced large millicurie quantities of [¹⁸F]DCFPyL while conforming to all standard US Pharmacopeia Chapter <823> acceptance testing criteria.     

Facile and improved synthesis of [11C]Me‐QNB

[¹¹C]Me‐QNB is a muscarinic acetylcholinergic receptor antagonist that has been used for the assessment of myocardial muscarinic receptors density in different cardiovascular pathologies. In the current technical note, we report a facile, highly efficient and fully automated method for the preparation of this radiotracer. The radiosynthesis was performed by reaction of [¹¹C]CH₃I with the desmethylated precursor (QNB) at room temperature using the captive solvent method. Excellent radiochemical yield (91.1 ± 2.4%, decay‐corrected) and radiochemical purity (>99.5%), and good specific activity (137 ± 5 GBq/µmol) were obtained when the purification was performed by reverse phase HPLC in overall synthesis time <31 min. Purification using solid‐phase extraction offered lower radiochemical yield (27.6 ± 3.1%, decay‐corrected) and radiochemical purity (>95%) but higher specific activity (244 ± 18 GBq/µmol) in shorter reaction times (<21 min). These results, especially concerning radiochemical yield, significantly improve those previously reported in which the reaction was performed in a vial and the purification step was based on ionic chromatography.     

Radiosynthesis of [11C]SL25.1188 via [11C]CO2 fixation for imaging monoamine oxidase B

Carbon‐11‐labelled (S)‐5‐methoxymethyl‐3‐[6‐(4,4,4‐trifluorobutoxy)benzo[d]isoxazol‐3‐yl]oxazolidin‐2‐[¹¹C]‐one ([¹¹C]SL25.1188), a promising reversibly binding radiotracer for imaging central monoamine oxidase B, was rapidly prepared via an intramolecular cyclization reaction in an automated one‐pot procedure directly from [¹¹C]CO₂, thereby precluding the use of [¹¹C]COCl₂. Formulated [¹¹C]SL25.1188 was isolated in 12 ± 1% uncorrected radiochemical yield, based on starting [¹¹C]CO₂, with a specific activity of 37 ± 2 GBq/µmol at the end of synthesis (30 min; n = 3). Radiochemical and enantiomeric purities were both >99%. The methodology described herein offers an efficient production of [¹¹C]SL25.1188 at ambient temperature and is suitable for human imaging studies.     

Regioselective F‐18 radiolabeling of AM694, a CB1 cannabinoid receptor ligand

[¹⁸F]AM694, [1‐(5‐[¹⁸F]fluoropentyl)‐1H‐indol‐3‐yl]‐(2‐iodophenyl)methanone, 1b , a potential radiotracer for imaging of cerebral cannabinoid receptor (CB₁), has been synthesized by no‐carrier‐added regioselective radiofluorination of the corresponding tosylate. [¹⁸F]AM694 was obtained in 20% radiochemical yield (non‐decay‐corrected) with a specific activity of 14 500 mCi/µmol, a radiochemical purity of > 99%, and a chemical purity of 95.5%. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of a 11C‐labelled taxane derivative by [1‐11C]acetylation

The ¹¹C‐labelling of the taxane derivative BAY 59‐8862 ( 1 ), a potent anticancer drug, was carried out as a module‐assisted automated multi‐step synthesis procedure. The radiotracer [¹¹C]1 was synthesized by reacting [1‐¹¹C]acetyl chloride ( 6 ) with the lithium salt of the secondary hydroxy group of precursor 3 followed by deprotection. After HPLC purification of the final product [¹¹C]1 , its solid‐phase extraction, formulation and sterile filtration, the decay‐corrected radiochemical yield of [¹¹C]1 was in the range between 12 and 23% (related to [¹¹C]CO₂; n=10). The total synthesis time was about 54 min after EOB. The radiochemical purity of [¹¹C]1 was greater than 96% and the chemical purity exceeded 80%. The specific radioactivity was 16.8±4.7 GBq/µmol (n=10) at EOS starting from 80 GBq of [¹¹C]CO₂. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis,labelling and first evaluation of [18F]R91150 as a serotonin 5‐HT2A receptor antagonist for PET

In psychiatric disorders such as anxiety, depression and schizophrenia, 5‐HT_2A receptors play an important role. In order to investigate them in vivo there is an increasing interest in selective and high‐affinity radioligands for receptor binding studies using positron emission tomography (PET). Since available radioligands have disadvantages, R91150, which is a selective and high‐affinity ligand for 5‐HT_2A receptors, was labelled with fluorine‐18. This was accomplished in six steps via 4‐[¹⁸F]fluorophenol and 1‐(3‐bromopropoxy)‐4‐[¹⁸F]fluorobenzene within 190 min starting from no‐carrier‐added [¹⁸F]fluoride. The overall radiochemical yield was 3.8±2% and the specific activity was at least 335 GBq/µmol at the end of the synthesis. First ex vivo studies in mice proved the uptake of [¹⁸F]R91150 in the brain. Radiometabolite studies revealed no radiometabolites in the brain, whereas in the plasma at least two could be detected 30 min p.i. Further preclinical studies are encouraged to evaluate the potential of this new 5‐HT_2A ligand as a radiotracer for PET. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of a radioiodinated thymidine phosphorylase inhibitor and its preliminary evaluation as a potential SPECT tracer for angiogenic enzyme expression

The expression of thymidine phosphorylase (TP) is strongly associated with angiogenesis in tumors and activation of antitumor agents. We designed a novel 5‐¹²⁵I‐labeled 6‐(2‐iminoimidazolidinyl)methyluracil hydrochloride ([¹²⁵I]5I6IMU‐HCl) to develop an effective radiotracer for in vivo assessment of TP expression in tumors and prognosis of cancer chemotherapy. Radiotracer synthesis was achieved by radioiodination of the precursor, 6‐(2‐iminoimidazolidinyl)methyluracil at the C‐5 position with NCS/radioiodide. After purification by HPLC, [¹²⁵I]5I6IMU‐HCl was obtained in high radiochemical yield with satisfactory specific activity. The radiotracer showed high inhibitory potency for the target enzyme and good stability in vivo. Copyright © 2008 John Wiley & Sons, Ltd.     

Efficient synthesis of [11C]befloxatone,a selective radioligand for the in vivo imaging of MAO‐A density using PET

Carbon‐11 labelled befloxatone ((5R)‐5‐(methoxymethyl)‐3‐[4‐[(3R)‐4,4,4‐trifluoro‐3‐hydroxybutoxy]phenyl]‐2‐oxazolidinone) is a reversible and selective monoamine oxidase‐A (MAO‐A) inhibitor and appears to be a new potent PET tracer for the in vivo imaging of MAO‐A density. In this paper, the radiosynthesis of befloxatone was investigated and orientated towards the preparation of multi milliCuries of radiotracer. Typically, using no‐carrier‐added [¹¹C]phosgene, 150–300 mCi (5.55–11.10 GBq) of [¹¹C]befloxatone was obtained within 20 min of radiosynthesis (including HPLC purification) with specific radioactivities ranging from 500 to 2000 mCi/µmol (18.5–74.0 GBq/µmol). The high efficiency of these radiosyntheses allows for multi‐injection protocols and kinetic approaches for absolute quantification of the tracer. Copyright © 2003 John Wiley & Sons, Ltd.     

Automated one‐step radiosynthesis of the CB1 receptor imaging agent [18F]MK‐9470

The fluorine‐18‐labeled positron emission tomography (PET) radiotracer [¹⁸F]MK‐9470 is a selective, high affinity inverse agonist that has been used to image the cannabinoid receptor type 1 in human brain in healthy and disease states. This report describes a simplified, one‐step [¹⁸F]radiofluorination approach using a GE TRACERlab FX_FN module for the routine production of this tracer. The one‐step synthesis, by [¹⁸F]fluoride displacement of a primary tosylate precursor, gives a six‐fold increase in yield over the previous two‐step method employing O‐alkylation of a phenol precursor with 1,2‐[¹⁸F]fluorobromoethane. The average radiochemical yield of [¹⁸F]MK‐9470 using the one‐step method was 30.3 ± 11.7% (n = 12), with specific activity in excess of 6 Ci/µmol and radiochemical purity of 97.2 ± 1.5% (n = 12), in less than 60 min. This simplified, high yielding, automated process was validated for routine GMP production of [¹⁸F]MK‐9470 for clinical studies.     

Synthesis of the phytohormone [11C]methyl jasmonate via methylation on a C18 Sep Pak™ cartridge

[¹¹C]labeled (±)‐methyl jasmonate was synthesized using a C₁₈ Sep Pak? at ～100°C to sustain a solid‐supported ¹¹C‐methylation reaction of sodium (±)‐jasmonate using [¹¹C]methyl iodide. After reaction, the Sep Pak was rinsed with acetone to elute the labeled product, and the solvent evaporated rendering [¹¹C]‐(±)‐methyl jasmonate at 96% radiochemical purity. The substrate, (±)‐jasmonic acid, was retained on the Sep Pak so further chromatography was unnecessary. Total synthesis time was 25 min from the end of bombardment (EOB) which included 15 min to generate [¹¹C]methyl iodide using the GE Medical Systems PET Trace MeI system, 5 min for reaction and extraction from the cartridge, and 5 min to reformulate the product for plant administration. An overall radiochemical yield (at EOB) of 17±4.3% was obtained by this process, typically producing 10 mCi of purified radiotracer. A specific activity of 0.5 Ci/µmol was achieved using a short 3 min cyclotron beam to produce the starting ¹¹C. Copyright © 2005 John Wiley & Sons, Ltd.