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.     

Automated radiosynthesis of the adenosine A2A receptor-targeting radiotracer [18F]FLUDA

[¹⁸F] FLUDA is a selective radiotracer for in vivo imaging of the adenosine A_2A receptor (A_2AR) by positron emission tomography (PET). Promising preclinical results obtained by neuroimaging of mice and piglets suggest the translation of [¹⁸F] FLUDA to human PET studies. Thus, we report herein a remotely controlled automated radiosynthesis of [¹⁸F] FLUDA using a GE TRACERlab FX2 N radiosynthesizer. The radiotracer was obtained by a one-pot two-step radiofluorination procedure with a radiochemical yield of 9±1%, a radiochemical purity of ≥99%, and molar activities in the range of 69–333 GBq/μmol at the end of synthesis within a total synthesis time of approx. 95 min (n = 16). Altogether, we successfully established a reliable and reproducible procedure for the automated production of [¹⁸F] FLUDA.     

Impact of dianionic and dicationic linkers on tumor uptake and biodistribution of [64Cu]Cu/NOTA peptide‐based gastrin‐releasing peptide receptors antagonists

In this study, we investigated for the first time the influence of 2‐aminoethyl‐piperazine‐1‐carboxylic acid (APCA) and amino‐hexanedioic‐1‐acid (AHDA) on tumor uptake and elimination kinetics of [⁶⁴Cu]‐radiolabeled gastrin releasing peptide receptors (GRPR) antagonists. Three GRPR antagonists containing the RM26 sequence were synthesized and conjugated with NOTA via different linkers (LK): polyethylene glycol (PEG–neutral), APCA (dicationic) or AHDA (dianionic). The NOTA‐LK‐RM26 peptides were radiolabeled with ⁶⁴Cu to assess their pharmacokinetic and positron emission tomography (PET) imaging properties using PC3 tumor‐bearing athymic nude mice. The inhibition constants (K_i) of the 3 ^natCu/NOTA‐LK‐RM26 peptides bearing PEG, dicationic and dianionic linkers were 0.98 ± 0.48 nM, 0.95 ± 0.21 nM, and 17.97 ± 2.79 nM, respectively. The [⁶⁴Cu] NOTA‐LK‐RM26 conjugates were prepared with labeling yields superior to 95% and specific activities of 67 to 77 TBq/mmol. The 3 radiopeptides were stable in vivo and showed GRPR‐specific uptake in pancreas with a very fast washout of this tissue observed for [⁶⁴Cu]‐NOTA‐AHDA‐RM26 peptide. Results from imaging studies displayed specific PC3 tumor uptake for both [⁶⁴Cu]‐NOTA‐APCA‐ and AHDA‐RM26, similar kidney elimination and fast liver washout. Considering their adequate imaging characteristics, [⁶⁴Cu]‐NOTA‐LK‐RM26 bearing APCA‐ and AHDA‐linkers are promising candidates for GRPR‐targeted PET imaging prostate cancer.     

A concisely automated synthesis of TSPO radiotracer [18F]FDPA based on spirocyclic iodonium ylide method and validation for human use

Fluorine-18 labeled N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ([¹⁸F]FDPA) is a potent and selective radiotracer for positron-emission tomography (PET) imaging of the translocator protein 18 kDa (TSPO). Our previous in vitro and in vivo evaluations have proven that this tracer is promising for further human translation. Our study addresses the need to streamline the automatic synthesis of this radiotracer to make it more accessible for widespread clinical evaluation and application. Here, we successfully demonstrate a one-step radiolabeling of [¹⁸F]FDPA based on a novel spirocyclic iodonium ylide (SCIDY) precursor using tetra-n-butyl ammonium methanesulfonate (TBAOMs), which has demonstrated the highest radiochemical yields and molar activity from readily available [¹⁸F]fluoride ion. The nucleophilic radiofluorination was completed on a GE TRACERlab FX2 N synthesis module, and the formulated [¹⁸F]FDPA was obtained in nondecay corrected (n.d.c) radiochemical yields of 15.6 ± 4.2%, with molar activities of 529.2 ± 22.5 GBq/μmol (14.3 ± 0.6 Ci/μmol) at the end of synthesis (60 minutes, n = 3) and validated for human use. This methodology facilitates efficient synthesis of [¹⁸F]FDPA in a commercially available synthesis module, which would be broadly applicable for routine production and widespread clinical PET imaging studies.     

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.     

Efficient in‐loop synthesis of high specific radioactivity [11C]carfentanil

The synthesis of the precursor for [¹¹C]carfentanil and the precursor labelling with ¹¹C have both been improved. The problem ‘bottleneck’ step in the carfentanil precursor synthesis, due to low chemical yield (14%) of intermediates nitrile into amide conversion, has been solved. Application of a H₂O₂/K₂CO₃/DMSO reaction method significantly increased the yield of this chemical transformation (up to 84%). A simple and straight‐forward synthesis of [¹¹C]carfentanil was achieved by combining in‐loop methylation of the ammonia salt of the precursor by [¹¹C]CH₃I, using tetrabutylammonium hydroxide as a base, with a previously developed product purification procedure using a C2 extraction disc. A decay corrected yield with respect to [¹¹C]CH₃I of [¹¹C]carfentanil was 64±12% (n=6) with the synthesis time of 21 min. The radiochemical purity was >98%. Comparatively high specific radioactivity of [¹¹C]carfentanil [11.2±4.8 Ci/μmol (EOS, n=5)] was partially attributed to the use of [¹¹C]methane target gas for production of carbon‐11 methyl iodide. Copyright © 2003 John Wiley & Sons, Ltd.     

cGMP production of the radiopharmaceutical [18F]MK‐6240 for PET imaging of human neurofibrillary tangles

Fluorine‐18–labelled 6‐(fluoro)‐3‐(1H‐pyrrolo[2,3‐c]pyridin‐1‐yl)isoquinolin‐5‐amine ([¹⁸F]MK‐6240) is a novel potent and selective positron emission tomography (PET) radiopharmaceutical for detecting human neurofibrillary tangles, which are made up of aggregated tau protein. Herein, we report the fully automated 2‐step radiosynthesis of [¹⁸F]MK‐6240 using a commercially available radiosynthesis module, GE Healthcare TRACERlab FX_FN. Nucleophilic fluorination of the 5‐diBoc‐6‐nitro precursor with potassium cryptand [¹⁸F]fluoride (K[¹⁸F]/K₂₂₂) was performed by conventional heating, followed by acid deprotection and semipreparative high‐performance liquid chromatography under isocratic conditions. The isolated product was diluted with formulation solution and sterile filtered under Current Good Manufacturing Practices, and quality control procedures were established to validate this radiopharmaceutical for human use. At the end of synthesis, 6.3 to 9.3 GBq (170‐250 mCi) of [¹⁸F]MK‐6240 was formulated and ready for injection, in an uncorrected radiochemical yield of 7.5% ± 1.9% (relative to starting [¹⁸F]fluoride) with a specific activity of 222 ± 67 GBq/μmol (6.0 ± 1.8 Ci/μmol) at the end of synthesis (90 minutes; n = 3). [¹⁸F]MK‐6240 was successfully validated for human PET studies meeting all Food and Drug Administration and United States Pharmacopeia requirements for a PET radiopharmaceutical. The present method can be easily adopted for use with other radiofluorination modules for widespread clinical research use.     

Radiosynthesis of a Bruton's tyrosine kinase inhibitor, [11C]Tolebrutinib,via palladium-NiXantphos-mediated carbonylation

Bruton's tyrosine kinase (BTK) is a key component in the B-cell receptor signaling pathway and is consequently a target for in vivo imaging of B-cell malignancies as well as in multiple sclerosis (MS) with positron emission tomography (PET). A recent Phase 2b study with Sanofi's BTK inhibitor, Tolebrutinib (also known as [a.k.a.] SAR442168, PRN2246, or BTK'168) showed significantly reduced disease activity associated with MS. Herein, we report the radiosynthesis of [¹¹C]Tolebrutinib ([¹¹C] 5 ) as a potential PET imaging agent for BTK. The N-[¹¹C]acrylamide moiety of [¹¹C] 5 was labeled by ¹¹C-carbonylation starting from [¹¹C]CO, iodoethylene, and the secondary amine precursor via a novel palladium-NiXantphos - mediated carbonylation protocol, and the synthesis was fully automated using a commercial carbon-11 synthesis platform (TracerMaker™, Scansys Laboratorieteknik). [¹¹C] 5 was obtained in a decay-corrected radiochemical yield of 37 ± 2% (n = 5, relative to starting [¹¹C]CO activity) in >99% radiochemical purity, with an average molar activity of 45 GBq/μmol (1200 mCi/μmol). We envision that this methodology will be generally applicable for the syntheses of labeled N-acrylamides.     

Novel 64Cu-Labeled CUDC-101 for in Vivo PET Imaging of Histone Deacetylases

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Synthesis of carbon‐14 labeled 4‐[4‐[2‐[2‐[bis(4‐chlorophenyl) methoxy]ethyl sulfonyl][1‐14C]ethoxy]phenyl]‐1,1,1‐trifluoro‐2‐butanone

Carbon‐14 labeled 4‐[4‐[2‐[2‐[bis(4‐chlorophenyl)methoxyethylsulfonyl] [1‐¹⁴C]ethoxy]phenyl]‐1,1,1‐trifluoro‐2‐butanone was prepared in a six step radioactive synthesis from 2‐bromo[1‐¹⁴C]acetic acid. The overall radiochemical yield was 2.2%. The specific activity of the final product was found to be 42μCi/mg with a radiochemical purity of >98%. Copyright © 2002 John Wiley & Sons, Ltd.     

Efficient synthesis and formulation of (R)‐(−)‐[11C]Deprenyl,a selective radioligand for the quantification of MAO‐B activity using PET

Carbon‐11 labeled (R)‐(?)‐Deprenyl is the tracer of reference for the quantification of monoamine oxidase (MAO)‐B activity with PET. In this paper, its radiosynthesis is re‐investigated and oriented towards the preparation of multi‐milliCuries of radiotracer. Typically, using no‐carrier‐added [¹¹C]methyl triflate as the alkylating agent, 140–190 mCi (5.1–7.0 GBq) of (R)‐(?)‐[¹¹C]Deprenyl was obtained within 30 min of radiosynthesis (including HPLC purification and formulation) with specific radioactivities ranging from 0.8 to 1.2 Ci/μmol (29.6–44.4 GBq/μmol). The high efficiency of these radiosyntheses allows for multi‐injection protocols and kinetic approaches for absolute quantification of the tracer. Copyright © 2002 John Wiley & Sons, Ltd.     

Simplified and robust one‐step radiosynthesis of [18F]DCFPyL via direct radiofluorination and cartridge‐based purification

[¹⁸F]DCFPyL is a clinical‐stage PET radiotracer used to image prostate cancer. This report details the efficient production of [¹⁸F]DCFPyL using single‐step direct radiofluorination, without the use of carboxylic acid‐protecting groups. Radiolabeling reaction optimization studies revealed an inverse correlation between the amount of precursor used and the radiochemical yield. This simplified approach enabled automated preparation of [¹⁸F]DCFPyL within 28 minutes using HPLC purification (26% ± 6%, at EOS, n = 4), which was then scaled up for large‐batch production to generate 1.46 ± 0.23 Ci of [¹⁸F]DCFPyL at EOS (n = 7) in high molar activity (37 933 ± 4158 mCi/μmol, 1403 ± 153 GBq/μmol, at EOS, n = 7). Further, this work enabled the development of [¹⁸F]DCFPyL production in 21 minutes using an easy cartridge‐based purification (25% ± 9% radiochemical yield, at EOS, n = 3).     

Automated radiosynthesis of [18F]SPA‐RQ for imaging human brain NK1 receptors with PET

[¹⁸F]SPA‐RQ is an effective radioligand for imaging brain neurokinin type‐1 (NK₁) receptors in clinical research and drug discovery with positron emission tomography. For the automated regular production of [¹⁸F]SPA‐RQ for clinical use in the USA under an IND we chose to use a modified commercial synthesis module (TRACERlab FX_F‐N; GE Medical Systems) with an auxiliary custom‐made robotic cooling–heating reactor, after evaluating several alternative radiosynthesis conditions. The automated radiosynthesis and its quality control are described here. [¹⁸F]SPA‐RQ was regularly obtained within 150 min from the start of radiosynthesis in high radiochemical purity (>99%) and chemical purity and with an overall decay‐corrected radiochemical yield of 15±2% (mean±S.D.; n=10) from cyclotron‐produced [¹⁸F]fluoride ion. The specific radioactivity of [¹⁸F]SPA‐RQ at the end of synthesis ranged from 644 to 2140 mCi/µmol (23.8–79.2 GBq/µmol). Copyright © 2005 John Wiley & Sons, Ltd.     

Radiosynthesis of [11C]paclitaxel

[¹¹C]paclitaxel, a potential solid tumor imaging agent, was synthesized by reacting [α‐¹¹C]benzoyl chloride with the primary amine precursor of paclitaxel. The time for synthesis, purification, and formulation was 38 min from end of bombardment with an average specific radioactivity of 49.9 GBq/μmol (1349 mCi/μmol) at end of synthesis. The average decay corrected radiochemical yield was 7% with greater than 99% radiochemical purity. Copyright © 2002 John Wiley & Sons, Ltd.     

Fully automated,high yielding production of N‐succinimidyl 4‐[18F]fluorobenzoate ([18F]SFB), and its use in microwave‐enhanced radiochemical coupling reactions

A General Electric Medical Systems (GEMS) Tracerlab FX_FN fluorine‐18 synthesis module has been reconfigured to allow rapid (45 min), fully automated production of N‐succinimidyl 4‐[¹⁸F]fluorobenzoate ([¹⁸F]SFB) using the established three‐step, one‐pot synthesis procedure. Purification is by sep‐pak only and [¹⁸F]SFB is routinely obtained in 38% non‐decay corrected yield,>1 Ci/µmol specific activity, and >95% radiochemical purity (n=20). Moreover, this report includes our preliminary research efforts into improving peptide coupling reactions with [¹⁸F]SFB using microwave‐enhanced radiochemistry. Reaction times can be reduced by>90%, when compared with traditional thermal reactions, with no significant effect on radiochemical reaction yield. Copyright © 2010 John Wiley & Sons, Ltd.     

Automated synthesis of (R)-[18F]MH.MZ on the iPhase Flexlab reaction platform

(R)-[¹⁸F]MH.MZ ([¹⁸F]MH.MZ) is a promising positron emission tomography (PET) radiotracer for in vivo study of the 5-HT_2A receptor. To facilitate clinical trials, a fully automated radiosynthesis procedure for [¹⁸F]MH.MZ was developed using commercially available materials on the iPhase Flexlab module. The overall synthesis time was 100 min with a radiochemical yield of 7 ± 0.9% (n = 3). The radiochemical purity was greater than 99% for [¹⁸F]MH.MZ with a molar activity of 361 ± 57 GBq/μmol (n = 3). The protocol described herein reliably provides [¹⁸F]MH.MZ that meets all relevant release criteria for a GMP radiopharmaceutical.     

Automated radiosynthesis of [11C]MTP38—a phosphodiesterase 7 imaging tracer—using [11C]hydrogen cyanide for clinical applications

We have developed 8-amino-3-(2S,5R-dimethyl-1-piperidyl)-[1,2,4]triazolo[4,3-a]pyrazine-5-[¹¹C]carbonitrile ([¹¹C]MTP38) as a positron emission tomography (PET) tracer for the imaging of phosphodiesterase 7. For the fully automated production of [¹¹C]MTP38 routinely and efficiently for clinical applications, we determined the radiosynthesis procedure of [¹¹C]MTP38 using [¹¹C]hydrogen cyanide ([¹¹C]HCN) as a PET radiopharmaceutical. Radiosynthesis of [¹¹C]MTP38 was performed using an automated ¹¹C-labeling synthesizer developed in-house within 40 min after the end of irradiation. [¹¹C]MTP38 was obtained with a relatively high radiochemical yield (33 ± 5.5% based on [¹¹C]CO₂ at the end of irradiation, decay-corrected, n = 15), radiochemical purity (>97%, n = 15), and molar activity (47 ± 12 GBq/μmol at the end of synthesis, n = 15). All the results of the quality control (QC) testing for the [¹¹C]MTP38 injection complied with our in-house QC and quality assurance specifications. We successfully automated the radiosynthesis of [¹¹C]MTP38 for clinical applications using an ¹¹C-labeling synthesizer and sterile isolator. Taken together, this protocol provides a new radiopharmaceutical [¹¹C]MTP38 suitable for clinical applications.     

Automated radiosynthesis of no‐carrier‐added 4‐[18F]fluoroiodobenzene: a versatile building block in 18F radiochemistry

4‐[¹⁸F]Fluoroiodobenzene ([¹⁸F]FIB) is a versatile building block in ¹⁸F radiochemistry used in various transition metal‐mediated C–C and C–N cross‐coupling reactions and [¹⁸F]fluoroarylation reactions. Various synthesis routes have been described for the preparation of [¹⁸F]FIB. However, to date, no automated synthesis of [¹⁸F]FIB has been reported to allow access to larger amounts of [¹⁸F]FIB in high radiochemical and chemical purity. Herein, we describe an automated synthesis of no‐carrier‐added [¹⁸F]FIB on a GE TRACERlab? FX automated synthesis unit starting from commercially available (4‐iodophenyl)diphenylsulfonium triflate as the labelling precursor. [¹⁸F]FIB was prepared in high radiochemical yields of 89 ± 10% (decay‐corrected, n = 7) within 60 min, including HPLC purification. The radiochemical purity exceeded 95%, and specific activity was greater than 40 GBq/µmol. Typically, from an experiment, 6.4 GBq of [¹⁸F]FIB could be obtained starting from 10.4 GBq of [¹⁸F]fluoride. Copyright © 2013 John Wiley & Sons, Ltd.     

High-yielding,automated radiosynthesis of [11C]martinostat using [11C]methyl triflate

Histone deacetylases (HDACs) mediate epigenetic mechanisms implicated in a broad range of central nervous system dysfunction, including neurodegenerative diseases and neuropsychiatric disorders. [¹¹C]Martinostat allows in vivo quantification of class I/IIb HDACs and may be useful for the quantification of drug–occupancy relationship, facilitating drug development for disease modifying therapies. The present study reports a radiosynthesis of [¹¹C]martinostat using [¹¹C]methyl triflate in ethanol, as opposed to the originally described synthesis using [¹¹C]methyl iodide and DMSO. [¹¹C]Methyl triflate is trapped in a solution of 2 mg of precursor 1 dissolved in anhydrous ethanol (400 μl), reacted at ambient temperature for 5 min and purified by high-performance liquid chromatography; 1.5–1.8 GBq (41–48 mCi; n = 3) of formulated [¹¹C]martinostat was obtained from solid-phase extraction using a hydrophilic–lipophilic cartridge in a radiochemical yield of 11.4% ± 1.1% (nondecay corrected to trapped [¹¹C]MeI), with a molar activity of 369 ± 53 GBq/μmol (9.97 ± 1.3 Ci/μmol) at the end of synthesis (40 min) and validated for human use. This methodology was used at our production site to produce [¹¹C]martinostat in sufficient quantities of activity to scan humans, including losses incurred from decay during pre-release quality control testing.     

The syntheses of [13C6] and [phenyl‐14C(U)]BMS‐816336, an inhibitor of 11β‐hydroxysteroid dehydrogenase type 1, for type 2 diabetes

Type 2 diabetes is a significant worldwide health problem. To support the development of BMS‐816336 as an inhibitor of 11β‐hydroxysteroid dehydrogenase type 1 for type 2 diabetes, the synthesis of carbon‐14 labeled material was required for use in metabolic profiling. [Phenyl‐¹⁴C(U)]BMS‐816336 was synthesized in 8 steps and 22% radiochemical yield from commercially available [¹⁴C(U)]bromobenzene. The radiochemical purity of [phenyl‐¹⁴C(U)]BMS‐816336 was 100% having a specific activity of 84.4 μCi/mg or 28.8 mCi/mmol for a total of 8.9 mCi. It was also necessary to synthesize [¹³C₆]BMS‐816336 for use as a liquid chromatography/mass spectrometry standard. [¹³C₆]BMS‐816336 was also prepared in 8 labeled steps in 26% yield from [¹³C₆]bromobenzene.