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Gallium-68-labeled FAPI-46 has recently been proposed as a novel positron emission tomography imaging probe to diagnose and monitor a wide variety of cancers. Promising results from several ongoing clinical trials have led to a soaring demand for this radiotracer. Typical [68Ga]Ga-FAPI-46 labeling protocols do not cope with multiple generator elutions, leaving radiopharmacies unable to scaleup the production and meet the demand. Here, we propose a robust and efficient automated radiosynthesis of [68Ga]Ga-FAPI-46 on the Trasis miniAllinOne synthesizer, featuring a prepurification step which allows multiple generator elutions and ensures compatibility with a wide range of gallium-68 generators. Our approach was to optimize the prepurification step by first testing five different cationic cartridge chemistries. Only the strong cationic exchange (SCX) cartridges tested had sufficient affinities for quantitative trapping of >99.9%, while the weak cationics did not exceed 50%. Packaging, rinsing, or flowing of the selected SCX cartridges was not noticeable, but improvements in fluidics managed to save time. Based on our previous development experience of [68Ga]Ga-FAPI-46, radiolabeling optimization was also carried out at different temperatures during 10 min. At temperatures above 100°C, radiochemical yield (RCY) > 80% was achieved without significantly increasing the chemical impurities (<5.5 μg mL-1). The optimized sequence was reproducibly conducted with three different brands of widely used generators (RCY >88%). A comparison with radiosyntheses carried out without prepurification steps was also conclusive in terms of RCY, radiochemical yield, and chemical purity. Finally, high-activity tests using elutions from three generators were also successful for these parameters. [68Ga]Ga-FAPI-46 was consistently obtained in good radiochemical yields (>89%, n = 3), and the final product quality was compliant with internal specifications based on European Pharmacopoeia. This process is suitable for GMP production and allows scalingup of routine productions, higher throughput, and, ultimately, better patient care. [ABSTRACT FROM AUTHOR]

A labeling technique was developed for the imidazoline I2 receptor ligand 2‐(3‐fluoro‐tolyl)‐4, 5‐dihydro‐1H‐imidazole (FTIMD) using Pd(0)‐mediated 11C‐carbomethoxylation with [11C]CO, followed by imidazoline ring formation with ethylenediamine‐trimethylaluminium (EDA‐AlMe3). To achieve this, [11C]CO was passed through a methanol (MeOH) solution containing 3‐fluoro‐4‐methylphenylboronic acid (1), palladium (II) acetate (Pd [OAc]2), triphenylphosphine (PPh3), and p‐benzoquinone (PBQ). The mixture was then heated at 65°C for 5 min. EDA was introduced into the reaction mixture, and MeOH was completely evaporated at temperatures exceeding 100°C. The dried reaction mixture was combined with an EDA‐AlMe (1:1) toluene solution and heated at 145°C for 10 min. Portions of the reaction mixture were analyzed through high‐performance liquid chromatography, resulting in [11C]FTIMD with 26% (n = 2) decay‐corrected radiochemical yield (RCY). This method could be utilized for various arylborons to produce [2‐11C]imidazolines 4a–h with RCYs ranging from low to moderate. Notably, [2‐11C]benazoline was obtained with a moderate RCY of 65%. The proposed technique serves as an alternative to the Grignard method, which uses [11C]CO to generate a [2‐11C]‐labeled imidazoline ring. [ABSTRACT FROM AUTHOR]

Velagliflozin is the active ingredient of the first oral liquid medication approved by the Food and Drug Administration for the treatment of diabetes in cats. This compound belongs to the known class of sodium-glucose cotransporter 2 inhibitors approved to treat diabetes in human. Here, we report the detailed synthesis of velagliflozin labeled with carbon 14 and carbon 13. [ABSTRACT FROM AUTHOR]

The radioligand [18F]FPEB, used for PET imaging of the brain's metabotropic glutamate receptor subtype 5 (mGluR5), undergoes a thorough validation process to ensure its safety, efficacy, and quality for clinical use. The process starts by optimizing the synthesis of [18F]FPEB to achieve high radiochemical yield and purity. This study focuses on optimizing the radiolabeling process using an aryl‐chloro precursor and validating the GMP production for clinical applications. Fully automated radiolabeling was achieved via one‐step nucleophilic substitution reaction. [18F]FPEB was produced and isolated in high radioactivity and radiochemical purity. Throughout the validation process, thorough quality control measures are implemented. Radiopharmaceutical batch release criteria are established, including testing for physical appearance, filter integrity, pH, radiochemical purity, molar activity, radiochemical identity, chemical impurity, structural identity, stability, residual solvent, sterility, and endotoxin levels. In conclusion, the validation of [18F]FPEB involved a comprehensive process of synthesis optimization, quality control, which ensure the safety, efficacy, and quality of [18F]FPEB, enabling its reliable use in clinical PET. Here, we successfully radiolabeled and validated [18F]FPEB using aryl‐chloro precursor according to GMP production for clinical application. [ABSTRACT FROM AUTHOR]

Gallium-68-labeled FAPI-46 has recently been proposed as a novel positron emission tomography imaging probe to diagnose and monitor a wide variety of cancers. Promising results from several ongoing clinical trials have led to a soaring demand for this radiotracer. Typical [68Ga]Ga-FAPI-46 labeling protocols do not cope with multiple generator elutions, leaving radiopharmacies unable to scale-up the production and meet the demand. Here, we propose a robust and efficient automated radiosynthesis of [68Ga]Ga-FAPI-46 on the Trasis miniAllinOne synthesizer, featuring a prepurification step which allows multiple generator elutions and ensures compatibility with a wide range of gallium-68 generators. Our approach was to optimize the prepurification step by first testing five different cationic cartridge chemistries. Only the strong cationic exchange (SCX) cartridges tested had sufficient affinities for quantitative trapping of >99.9%, while the weak cationics did not exceed 50%. Packaging, rinsing, or flowing of the selected SCX cartridges was not noticeable, but improvements in fluidics managed to save time. Based on our previous development experience of [68Ga]Ga-FAPI-46, radiolabeling optimization was also carried out at different temperatures during 10 min. At temperatures above 100°C, radiochemical yield (RCY) > 80% was achieved without significantly increasing the chemical impurities (88%). A comparison with radiosyntheses carried out without prepurification steps was also conclusive in terms of RCY, radiochemical yield, and chemical purity. Finally, high-activity tests using elutions from three generators were also successful for these parameters. [68Ga]Ga-FAPI-46 was consistently obtained in good radiochemical yields (>89%, n = 3), and the final product quality was compliant with internal specifications based on European Pharmacopoeia. This process is suitable for GMP production and allows scaling-up of routine productions, higher throughput, and, ultimately, better patient care.

While automated modules for F‐18 and C‐11 radiosyntheses are standardized with features such as multiple reactors, vacuum connection and semi‐preparative HPLC, labeling and processing of compounds with radiometals such as Zr‐89, Lu‐177 and Ac‐225 often do not require complex manipulations and are frequently performed manually by a radiochemist. These procedures typically involve transferring solutions to and from vials using pipettes followed by heating of the reaction mixture, and do not require all the features found in most commercial automated synthesis units marketed as F‐18 or C‐11 modules. Here we present an efficient automated method for performing radiosyntheses involving radiometals by adapting a commercially available robotic pipettor originally developed for high‐throughput processing of biological samples. While a robotic pipettor is less costly than a radiosynthesis module, it holds many similar advantages over manual radiosynthesis such as minimization of operator error, lower operator exposure rates, and abbreviated synthesis times, among others. To demonstrate the feasibility of using the OpenTrons OT‐2 robotic pipettor to perform automated radiosyntheses, we radiolabeled and formulated 177Lu‐PSMA‐617 and 225Ac‐PSMA‐617 on the system. The OT‐2 was then used to help streamline the quality control process for both products, further minimizing manual handling by and exposure to the radiochemist. [ABSTRACT FROM AUTHOR]

14-(R,S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA) is a radiocompound for imaging the fatty acid circulation by positron emission tomography. A revived interest in imaging of lipid metabolism led us to a constant tracer production over three years, initially using a conventional vessel-based synthesizer and later transitioning to the cassette-based Elixys synthesizer. On the Elixys module, the radiochemical yield of [18F]FTHA could be increased by more than two times, reaching 13.01 ± 5.63% at the end of the synthesis, while maintaining necessary quality control results. [ABSTRACT FROM AUTHOR]

The σ‐1 receptor is a non‐opioid transmembrane protein involved in various human pathologies including neurodegenerative diseases, inflammation, and cancer. The previously published ligand [18F]FTC‐146 is among the most promising tools for σ‐1 molecular imaging by positron emission tomography (PET), with a potential for application in clinical diagnostics and research. However, the published six‐ or four‐step synthesis of the tosyl ester precursor for its radiosynthesis is complicated and time‐consuming. Herein, we present a simple one‐step precursor synthesis followed by a one‐step fluorine‐18 labeling procedure that streamlines the preparation of [18F]FTC‐146. Instead of a tosyl‐based precursor, we developed a one‐step synthesis of the precursor analog AM‐16 containing a chloride leaving group for the SN2 reaction with 18F‐fluoride. 18F‐fluorination of AM‐16 led to a moderate decay‐corrected radiochemical yield (RCY = 7.5%) with molar activity (Am) of 45.9 GBq/μmol. Further optimization of this procedure should enable routine radiopharmaceutical production of this promising PET tracer. [ABSTRACT FROM AUTHOR]

Microfluidic technology is a highly efficient technique used in positron emission tomography (PET) radiochemical synthesis. This approach enables the precise control of reactant flows and reaction conditions, leading to improved yields and reduced synthesis time. The synthesis of two radiotracers, L-[11C]methionine and [11C]choline, was performed, using a microfluidic cassette and an iMiDEVTM module by employing a dose-on-demand approach for the synthesis process. We focused on optimizing the precursor amounts and radiosynthesis on the microfluidic cassette. L-[11C]methionine and [11C]choline were synthesized using a microreactor filled with a suitable resin for the radiochemical reaction. Trapping of the [11C]methyl iodide, its reaction, and solid-phase extraction purification were performed on a microreactor, achieving radiochemical yields of >80% for L-[11C]methionine and >60% for [11C]choline (n = 3). The total synthesis time for both the radiotracers was approximately 20 min. All quality control tests complied with the European Pharmacopeia standards. The dose-on-demand model allows for real-time adaptation to patient schedules, making it suitable for preclinical and clinical settings. Precursor optimization enhanced the cost efficiency without compromising the yield. The importance of dose-on-demand synthesis and optimized precursor utilization to produce L-[11C]methionine and [11C]choline was emphasized in this study. The results demonstrated the feasibility of dose-on-demand adaptations for clinical applications with reduced precursor quantities and high radiochemical yields. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder with increasing global prevalence and accounts for over half of all dementia cases. Early diagnosis is paramount for not only the management of the disease, but also for the development of new AD treatments. The current golden standard for diagnosis is performed by positron emission tomography (PET) scans with the tracer [11C]Pittsburg Compound B ([11C]PiB), which targets amyloid beta protein (Aβ) that builds up as plaques in the brain of AD patients. The increasing demand for AD diagnostics is in turn expected to drive an increase in [11C]PiB-PET scans and the setup of new [11C]PiB production lines at PET centers globally. Here, we present the [11C]PiB production setups, experiences, and use from four Danish PET facilities and discuss the challenges and potential pitfalls of [11C]PiB production. We report on the [11C]PiB production performed with the 6-OH-BTA-0 precursor dissolved in either dry acetone or 2-butanone and by using either [11C]CO2 or [11C]CH4 as 11C- precursors on three different commercial synthesis modules: TracerLab FX C Pro, ScanSys, or TracerMaker. It was found that the [11C]CO2 method gives the highest radioactive yield (1.5 to 3.2 GBq vs. 0.8 ± 0.3 GBq), while the highest molar activity (98.0 ± 61.4 GBq/μmol vs. 21.2 to 95.6 GBq/μmol) was achieved using [11C]CH4. [11C]PiB production with [11C]CO2 on a TracerLab FX C Pro offered the most desirable results, with the highest yield of 3.17 ± 1.20 GBq and good molar activity of 95.6 ± 44.2 GBq/μmol. Moreover, all reported methods produced [11C]PiB in quantities suitable for clinical applications, thus providing a foundation for other PET facilities seeking to establish their own [11C]PiB production. [ABSTRACT FROM AUTHOR]

σ1 receptors play a crucial role in various neurological and neurodegenerative diseases including pain, psychosis, Alzheimer's disease, and depression. Spirocyclic piperidines represent a promising class of potent σ1 receptor ligands. The relationship between structural modifications and σ1 receptor affinity and selectivity over σ2 receptors led to the 2-fluoroethyl derivative fluspidine (2, Ki = 0.59 nM). Enantiomerically pure (S)-configured fluspidine ((S)-2) was prepared by the enantioselective reduction of the α,β-unsaturated ester 23 with NaBH4 and the enantiomerically pure co-catalyst (S,S)-24. The pharmacokinetic properties of both fluspidine enantiomers (R)-2 and (S)-2 were analyzed in vitro. Molecular dynamics simulations revealed very similar interactions of both fluspidine enantiomers with the σ1 receptor protein, with a strong ionic interaction between the protonated amino moiety of the piperidine ring and the COO- moiety of glutamate 172. The 18F-labeled radiotracers (S)-[18F]2 and (R)-[18F]2 were synthesized in automated syntheses using a TRACERlab FX FN synthesis module. High radiochemical yields and radiochemical purity were achieved. Radiometabolites were not found in the brains of mice, piglets, and rhesus monkeys. While both enantiomers revealed similar initial brain uptake, the slow washout of (R)-[18F]2 indicated a kind of irreversible binding. In the first clinical trial, (S)-[18F]2 was used to visualize σ1 receptors in the brains of patients with major depressive disorder (MDD). This study revealed an increased density of σ1 receptors in cortico-striato-(para)limbic brain regions of MDD patients. The increased density of σ1 receptors correlated with the severity of the depressive symptoms. In an occupancy study with the PET tracer (S)-[18F]2, the selective binding of pridopidine at σ1 receptors in the brain of healthy volunteers and HD patients was shown. [ABSTRACT FROM AUTHOR]

The aim of this study was to measure the brain penetrance and kinetics of BIIB104, a first-in-class AMPA receptor potentiator developed for cognitive impairment associated with schizophrenia. It was recently halted in phase 2 clinical development, and there are a lack of tools to directly measure AMPA receptor engagement. To achieve this, the drug candidate was radiolabeled with carbon-11, and its brain penetrance and kinetics were measured in non-human primates via dynamic PET scans. Radiolabeling was achieved through a three-step nucleophilic [11C]cyanation reaction in one pot, resulting in the high radioactivity and radiochemical purity (>99%) of [11C]BIIB104. The study found that [11C]BIIB104 entered the non-human primate brains at 4–5% ID at peak, with a homogeneous distribution. However, a mild regional heterogeneity was observed in the thalamus. The lack of conclusive evidence for a change in regional values after BIIB104 dosing suggests that any specific binding component of BIIB104 is negligible compared to the free and non-specific components in the living brain. Overall, the study demonstrated high brain uptake with minor variability in [11C]BIIB104 distribution across various brain regions, its kinetics were consistent with those of passive diffusion, and the dominating components were the free concentration and non-specific binding. This information is valuable for understanding the potential effects and mechanisms of BIIB104 in the brain. [ABSTRACT FROM AUTHOR]

The α4β2 nicotinic acetylcholine receptor (nAChR) ligand 2‐[18F]fluoro‐3‐[2‐((S)‐3‐pyrrolinyl)methoxy]pyridine ([18F]nifene) has been synthesized in 10% decay‐corrected radiochemical yield using the IBA Synthera® platform (IBA Cyclotron Solutions, Louvain‐la‐Neuve, Belgium) with an integrated fluidic processor (IFP). Boc‐nitronifene served as the precursor, and 20% trifluoroacetic acid (TFA) was used to deprotect the Boc‐group after radiolabeling. By omitting the solvent extraction step after radiolabeling, the process was simplified to a single step with no manual intervention. [18F]Nifene was obtained in decay‐corrected radiochemical yields of 10 ± 2% (n = 20) and radiochemical purity >99%. Typical specific radioactivities of 2700–4865 mCi/μmole (100–180 GBq/μmol) were measured at the end of synthesis; total synthesis times were about 1 h 40 min. [ABSTRACT FROM AUTHOR]

A novel synthetic approach toward pinacol boronate used as a precursor in the recent radiosynthesis of [18F]rucaparib is described in this study. The Heck reaction of an ortho‐iodoaniline derivative bearing a chloride group at the meta‐position with acrylonitrile produced the desired (E)‐2‐aminocinnamonitrile derivative. The subsequent cyanide‐catalyzed imino‐Stetter reaction of aldimine derived from the obtained 2‐aminocinnamonitrile and aldehyde afforded the required trisubstituted indole‐3‐acetonitrile. The reduction of the nitrile group with cobalt boride followed by the construction of an azepinone scaffold generated indoloazepinone bearing a chloride substituent at the C6‐position of the indole scaffold. The Suzuki–Miyaura borylation of the chloride substituent produced pinacol boronate previously used in the synthesis of [18F]rucaparib. Detailed outcomes of different approaches using different 2‐aminocinnamonitriles were discussed as well. [ABSTRACT FROM AUTHOR]

CRANAD‐102, a selective near‐infrared fluorescent tracer targeting soluble amyloid‐β (Aβ) species, has recently attracted attention due to its potential to be used as a diagnostic tool for early stages of Alzheimer's disease (AD). Development of a positron emission tomography (PET) tracer based on CRANAD‐102 could as such allow to noninvasively study soluble and protofibrillar species of Aβ in humans. These soluble and protofibrillar species are thought to be responsible to cause AD. Within this work, we successfully 11C‐labeled CRANAD‐102 via a Suzuki–Miyaura reaction in a RCС of 48 ± 9%, with a RCP of >96% and a molar activity (Am) of 25 ± 7 GBq/μmol. Future studies have to be conducted to evaluate if [11C]CRANAD‐102 can be used to detect soluble protofibrils in vivo and if [11C]CRANAD‐102 can be used to detect AD earlier as possible with current diagnostics. [ABSTRACT FROM AUTHOR]

Abstract Background Fluorine‐18 labeled N‐(4‐chloro‐3‐(((fluoro‐18F)methyl‐d2)thio)phenyl)picolinamide, [18F]mG4P027, is a potent positron emission tomography (PET) radiotracer for mGluR4. Our previous in vitro and in vivo evaluations have demonstrated that this tracer is promising for further translational studies. However, automated radiosynthesis process poses significant challenges that need to be addressed. Methods The automated radiosynthesis was performed using the TRACERlab FX2N module, which comprises two distinct reactors capable of accommodating the two‐step reactions. Several problem‐solving strategies were employed to overcome challenges during the automation process. This included modifications to the reaction solvents, reaction conditions, use of a scavenger, drying methods, and the handling of the precursor. Results The use of n‐Bu4NN3 for scavenging excess compound 1 along with an efficient drying procedure played a key role in the success of the radiosynthesis. The water was successfully removed by using a different duct to overcome the water sensitivity for the second reaction. Conclusions Significant modifications were made to the manual process by carefully examining this process and addressing the root causes of the challenges associated with its automation. We successfully implemented automated radiosynthesis using the TRACERlab FX2N module and consequently, obtained a high‐purity radiolabeled [18F]mG4P027 in high yield, meeting the requirements for future human studies.

(R)‐2‐(4‐(Benzo[d]oxazol‐2‐yl)piperazin‐1‐yl)‐4‐((tetrahydro‐2H‐pyran‐4‐yl)amino)‐6,7‐dihydrothieno[3,2‐d]pyrimidine 5‐oxide (1) and (R)‐2‐(4‐(4‐chlorophenoxy)piperidin‐1‐yl)‐4‐((tetrahydro‐2H‐pyran‐4‐yl)amino)‐6,7‐dihydrothieno[3,2‐d]pyrimidine 5‐oxide (2) are two potent and selective inhibitors of phosphodiesterase type 4 (PDE4). In this manuscript, we report the detailed synthesis of these two compounds labeled with carbon 14 and with stable isotopes. The core (R)‐4‐((tetrahydro‐2H‐pyran‐4‐yl)amino)‐6,7‐dihydrothieno[3,2‐d]pyrimidine 5‐oxide is common in both inhibitors. In the radioactive synthesis, the carbon 14 atom was introduced in the benzoxazole moiety using [14C]carbon disulfide to obtain [14C]‐1 in five steps at a 55% overall yield. [14C]Urea was used to incorporate the carbon 14 atom in two steps in the dihydrothieno[3,2‐d]pyrimidine intermediate, which was then transformed in four more steps to [14C]‐2 at a 30% overall yield. Both compounds were isolated with specific activities higher than 54 mCi/mmol, radio‐ and chemical‐purities higher than 99%, and with excellent enantiomeric excess. In the stable isotope synthesis, [2H8]piperazine was used to prepare [2H8]‐1 in three steps in 72% overall yield, while [13C6]phenol was used to prepare [13C6]‐2 in four steps in 18% overall yield. [ABSTRACT FROM AUTHOR]

The radiotracer 1‐(2‐[18F]fluoroethyl)‐L‐tryptophan (L‐[18F]FETrp or [18F]FETrp) is a substrate of indoleamine 2,3‐dioxygenase, the initial and key enzyme of the kynurenine pathway associated with tumoral immune resistance. In preclinical positron emission tomography studies, [18F]FETrp is highly accumulated in a wide range of primary and metastatic cancers, such as lung cancer, prostate cancer, and gliomas. However, the clinical translation of this radiotracer into the first‐in‐human trial has not been reported, partially due to its racemization during radiofluorination which renders the purification of the final product challenging. However, efficient purification is essential for human studies in order to assure radiochemical and enantiomeric purity. In this work, we report a fully automated radiosynthesis of [18F]FETrp on a Synthra RNPlus research module, including a one‐pot two steps radiosynthesis, dual independent chiral and reverse‐phase semipreparative high‐performance liquid chromatography purifications, and solid‐phase extraction‐assisted formulation. The presented approach has led to its Investigational New Drug application and approval that allows the testing of this tracer in humans. [ABSTRACT FROM AUTHOR]

The high rate of incidence and mortality caused by breast cancer encourage urgent research to immediately develop new diagnostic and therapeutic agents for breast cancer. Alpha mangostin (AM) is a natural compound reported to have anti-breast cancer properties. Its electron-donating groups structure allows it to be labeled with an iodine-131 radioisotope to develop a candidate of a diagnostic and therapeutic agent for breast cancer. This study aims to prepare the [131I]Iodine-α-mangostin ([131I]I-AM) and evaluate its stability, lipophilicity, and cellular uptake in breast cancer cell lines. The [131I]I-AM was prepared by direct radiosynthesis with Chloramine-T method in two conditions (A: AM dissolved in NaOH, B: AM dissolved in ethanol). Reaction time, pH, and mass of the oxidizing agent were optimized as crucial parameters that affected the radiosynthesis reaction. Further analysis was conducted using the radiosynthesis conditions with the highest radiochemical purity (RCP). Stability tests were carried out at three storage conditions, including −20, 2, and 25 °C. A cellular uptake study was performed in T47D (breast cancer cell line) and Vero cells (noncancerous cell line) at various incubation times. The results show that the RCP values of [131I]I-AM under conditions A and B were 90.63 ± 0.44 and 95.17 ± 0.80% (n = 3), respectively. In the stability test, [131I]I-AM has an RCP above 90% after three days of storage at −20 °C. A significant difference was obtained between [131I]I-AM uptake in T47D and Vero cells. Based on these results, [131I]I-AM has been prepared with high RCP, stable at −20 °C, and specifically uptaken by breast cancer cell lines. Biodistribution evaluations in animals are recommended as further research in developing [131I]I-AM as a diagnostic and therapeutic agent for breast cancer. [ABSTRACT FROM AUTHOR]

The generation of amyloid beta peptides that aggregate in the brain is believed to play a major role in Alzheimer's disease. In theory, the inhibition of beta‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1), which catalyzes the initial rate‐limiting step in amyloid beta production, may slow or stop Alzheimer's disease. Herein, we report the preparation of two potent BACE1 inhibitors, BI 1147560 (1) and BI 1181181 (2), labeled with carbon‐14 and with deuterium. The use of advanced key chiral intermediates like 3 and 5 shortened the carbon‐14 syntheses of these two compounds to five and six steps, respectively, and helped in preparing them with very high chemical purity and enantiomeric excess without deviating from the process chemistry route. For the deuterium synthesis, oxetan‐3‐ylmethanamine [2H6]‐7 and 2‐fluoro‐2‐methylpropan‐1‐amine [2H6]‐9 were prepared then used with the chiral intermediate 5 to furnish deuterium labeled 1 and 2, respectively. [ABSTRACT FROM AUTHOR]

(R)‐4‐((R)‐1‐((6‐(1‐[tert‐butyl]‐1H‐pyrazol‐4‐yl)‐2‐methyl‐2H‐pyrazolo[3,4‐d]pyridin‐4‐yl)oxy)ethyl)pyrrolidin‐2‐one (BI 894416, 1) and (R)‐4‐((R)‐1‐((6‐(1‐[tert‐butyl]‐1H‐pyrazol‐4‐yl)‐2,3‐dimethyl‐2H‐indazol‐4‐yl)oxy)ethyl)pyrrolidin‐2‐one (BI 1342561, 2) are two new potent and selective spleen tyrosine kinase inhibitors developed to treat severe asthma. Both compounds have similar structures and they differ only in the bicyclic moiety 2‐methyl‐2H‐pyrazolo[4,3‐c]pyridine in 1 versus 2,3‐dimethyl‐2H‐indazole in 2. In the carbon 14 synthesis, 1‐(1‐[tert‐butyl]‐1H‐pyrazol‐4‐yl)ethan‐1‐one‐1‐14C ([14C]‐8) was prepared from the cyanation of 4‐bromopyrazole using zinc [14C]cyanide followed by methyl lithium addition on the nitrile group. The enolate of [14C]‐8 was then used to access these two bicyclic moieties via pyrano‐pyrazoles [14C]‐11 and [14C]‐12, which were further transformed in few more steps to [14C]‐(1) and [14C]‐2. Both inhibitors contain a tert‐butyl group. Introducing tert‐butyl‐d9 will not only provide internal standards for bioanalytical studies, but it is also expected to slow down the metabolism of these two compounds. Most of the metabolites of compound 1, for example, are the result of tert‐butyl oxidation, like alcohol 3, acid 4, and the further N‐demethylation of 4 to 5. The detailed preparation of these deuterium‐labeled metabolites is also described. [ABSTRACT FROM AUTHOR]

14-(R,S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA) is a radiocompound for imaging the fatty acid circulation by positron emission tomography. A revived interest in imaging of lipid metabolism led us to a constant tracer production over three years, initially using a conventional vessel-based synthesizer and later transitioning to the cassette-based Elixys synthesizer. On the Elixys module, the radiochemical yield of [18F]FTHA could be increased by more than two times, reaching 13.01 ± 5.63% at the end of the synthesis, while maintaining necessary quality control results.

Alzheimer’s disease (AD) is a neurodegenerative disorder with increasing global prevalence and accounts for over half of all dementia cases. Early diagnosis is paramount for not only the management of the disease, but also for the development of new AD treatments. The current golden standard for diagnosis is performed by positron emission tomography (PET) scans with the tracer [11C]Pittsburg Compound B ([11C]PiB), which targets amyloid beta protein (Aβ) that builds up as plaques in the brain of AD patients. The increasing demand for AD diagnostics is in turn expected to drive an increase in [11C]PiB-PET scans and the setup of new [11C]PiB production lines at PET centers globally. Here, we present the [11C]PiB production setups, experiences, and use from four Danish PET facilities and discuss the challenges and potential pitfalls of [11C]PiB production. We report on the [11C]PiB production performed with the 6-OH-BTA-0 precursor dissolved in either dry acetone or 2-butanone and by using either [11C]CO2 or [11C]CH4 as 11C- precursors on three different commercial synthesis modules: TracerLab FX C Pro, ScanSys, or TracerMaker. It was found that the [11C]CO2 method gives the highest radioactive yield (1.5 to 3.2 GBq vs. 0.8 ± 0.3 GBq), while the highest molar activity (98.0 ± 61.4 GBq/μmol vs. 21.2 to 95.6 GBq/μmol) was achieved using [11C]CH4. [11C]PiB production with [11C]CO2 on a TracerLab FX C Pro offered the most desirable results, with the highest yield of 3.17 ± 1.20 GBq and good molar activity of 95.6 ± 44.2 GBq/μmol. Moreover, all reported methods produced [11C]PiB in quantities suitable for clinical applications, thus providing a foundation for other PET facilities seeking to establish their own [11C]PiB production.

Microfluidic technology is a highly efficient technique used in positron emission tomography (PET) radiochemical synthesis. This approach enables the precise control of reactant flows and reaction conditions, leading to improved yields and reduced synthesis time. The synthesis of two radiotracers, L-[11C]methionine and [11C]choline, was performed, using a microfluidic cassette and an iMiDEVTM module by employing a dose-on-demand approach for the synthesis process. We focused on optimizing the precursor amounts and radiosynthesis on the microfluidic cassette. L-[11C]methionine and [11C]choline were synthesized using a microreactor filled with a suitable resin for the radiochemical reaction. Trapping of the [11C]methyl iodide, its reaction, and solid-phase extraction purification were performed on a microreactor, achieving radiochemical yields of >80% for L-[11C]methionine and >60% for [11C]choline (n = 3). The total synthesis time for both the radiotracers was approximately 20 min. All quality control tests complied with the European Pharmacopeia standards. The dose-on-demand model allows for real-time adaptation to patient schedules, making it suitable for preclinical and clinical settings. Precursor optimization enhanced the cost efficiency without compromising the yield. The importance of dose-on-demand synthesis and optimized precursor utilization to produce L-[11C]methionine and [11C]choline was emphasized in this study. The results demonstrated the feasibility of dose-on-demand adaptations for clinical applications with reduced precursor quantities and high radiochemical yields.

The aim of this study was to measure the brain penetrance and kinetics of BIIB104, a first-in-class AMPA receptor potentiator developed for cognitive impairment associated with schizophrenia. It was recently halted in phase 2 clinical development, and there are a lack of tools to directly measure AMPA receptor engagement. To achieve this, the drug candidate was radiolabeled with carbon-11, and its brain penetrance and kinetics were measured in non-human primates via dynamic PET scans. Radiolabeling was achieved through a three-step nucleophilic [11C]cyanation reaction in one pot, resulting in the high radioactivity and radiochemical purity (>99%) of [11C]BIIB104. The study found that [11C]BIIB104 entered the non-human primate brains at 4–5% ID at peak, with a homogeneous distribution. However, a mild regional heterogeneity was observed in the thalamus. The lack of conclusive evidence for a change in regional values after BIIB104 dosing suggests that any specific binding component of BIIB104 is negligible compared to the free and non-specific components in the living brain. Overall, the study demonstrated high brain uptake with minor variability in [11C]BIIB104 distribution across various brain regions, its kinetics were consistent with those of passive diffusion, and the dominating components were the free concentration and non-specific binding. This information is valuable for understanding the potential effects and mechanisms of BIIB104 in the brain.

Radiosynthesized silver nanoparticles (AgNPs) offer benefits for treatment of chronic colon inflammation due to their anti-inflammatory activity. Targeted delivery of AgNPs to the colon allows topical treatment at high concentration but at reduced systemic side effects. Meanwhile, related to drug administration, oral route is a common method. However, the physiology of the gastrointestinal (GI) tract limits the AgNPs ability to achieve their therapeutic level. This is specifically related to the acidic environment of the stomach and mucus layer of the GI tract. Concurently, alginates are one of the most extensively explored biomaterial classes for drug delivery system due to its biocompatibility, gel-forming ability at mild condition, anionic nature, sensitivity, and mucoadhesiveness. In this review we provide an overview of appropriate features of alginates as capping agent for oral delivery of radiosynthesized AgNPs to the colon. As capping agents, alginates play multiple roles specific to its processing stages, i.e., radiosynthesis, stabilization of nanoparticle system, and oral colon delivery devices of AgNPs. Additionally, we describe outstanding features of alginates as capping agents for drug delivery device as well as the positive contributions of radiation processing on improving the functional effects of alginate.

CuI‐mediated 11C‐cyanation was evaluated by synthesizing [11C]perampanel ([11C]5) as a model compound and compared with previous reports. To a DMF solution with 5′‐(2‐bromophenyl)‐1′‐phenyl‐[2,3′‐bipyridin]‐6′(1′H)‐one (4) and CuI, [11C]NH4CN in a stream of ammonia/nitrogen (5:95, v/v) gas was bubbled. Subsequently, the reaction mixture was heated at 180°C for 5 min. After HPLC purification, [11C]5 was obtained in 7.2 ± 1.0% (n = 4) non‐decay corrected radiochemical yield with >99% radiochemical purity and a molar activity of 98 ± 28 GBq/μmol. In vivo evaluations of [11C]5 were performed using small animals. PET scans to check the kinetics of [11C]5 in the whole body of mice suggested that [11C]5 spreads rapidly into the brain, heart, and lungs and then accumulates in the small intestine. To evaluate the performance of CuI‐mediated 11C‐cyanation reaction, bromobenzene (6a) was selected as the model compound; however, it failed. Therefore, optimization of the reaction conditions has been performed, and consequently, the addition of K2CO3 and prolonging the reaction time improved the radiochemical yield about double. With this improved method, CuI‐mediated 11C‐cyanation of various (hetero)aromatic bromides was performed to exhibit the tolerance of most functional groups and to provide 11C‐cyanated products in good to moderate radiochemical yields. [ABSTRACT FROM AUTHOR]

We report here the detailed radiosynthesis of [18F]mG4P027, a metabotropic glutamate receptor 4 (mGluR4) PET radiotracer, which showed superior properties to the currently reported mGluR4 radiotracers. The radiosynthesis in the automated system has been challenging, therefore we disclose here the major limiting factors for the synthesis via step‐by‐step examination. And we hope this thorough study will help its automation for human use in the future. [ABSTRACT FROM AUTHOR]

[18F]F-DOPA is widely used in PET diagnostics. Diseases diagnosed with this tracer are schizophrenia, Parkinson's disease, gliomas, neuroendocrine tumors, pheochromocytomas, and pancreatic adenocarcinoma. It should be noted that the [18F]F-DOPA tracer has been known for over 30 years. However, the methods of radiosynthesis applied in the past did not allow its clinical use due to low efficiency and purity. Currently, in the market, one encounters different types of radiosynthesis using the fluorine 18F isotope and variants of the same method. The synthesis and its modifications were carried out using a Raytest Synchrom R&D module. The synthesis consists of the following steps: (a) binding of the fluoride anion 18F− on an anion exchange column; (b) elution with TBAHCO3−; (c) nucleophilic fluorination to the ABX 1336 precursor; (d) purification of the intermediate product on the C18ec column; (e) Baeyer–Villiger oxidation; (f) hydrolysis; and (gfinal purification of the crude product on a semipreparative column. The nucleophilic synthesis of [18F]F-DOPA was successfully performed in 120 min, using the ABX 1336 precursor on the Raytest SynChrom R&D module, with a radiochemical yield (RCY) of 15%, radiochemical purity (RCP) ≥ 97%, and enantiomeric purity (ee) ≥ 96%. [ABSTRACT FROM AUTHOR]

Erianin is an active constituent of Dendrobium candidum. In this work, 18F-fluoroethoxylerianin ([18F]FEE), a 18F-Labeled erianin analogue, was designed and synthesized to evaluate the properties of erianin and related analogues by in vivo PET imaging. The initial product was separated and purified by liquid-phase separation module Explora LC and simple homemade solid-phase extraction, and high purity [18F]FEE was finally obtained. The radiochemical purity of [18F]FEE was determined by Radio-TLC and Radio-HPLC. [18F]FEE showed good stability in normal saline and serum, and could be quickly eliminated from mice. Cell experiments, biological distribution, and small-animal PET/CT further showed that [18F]FEE had a high uptake rate in HepG2 tumor cells, and showed good imaging ability in a HepG2 tumor model. The results of this study indicate that the synthesized 18F-labeled erianin analogue is an effective new probe for positron emission tomography (PET) imaging of HepG2 hepatocellular carcinoma, which provides an intuitive and reliable theoretical basis for the development of erianin as an anticancer drug.

[18F]fluorocholine ([18F]FCH) is an effective tracer for the imaging of different tumors of human brain, lung, or prostate. The purpose of this study was to evaluate the radiochemical yield and quality of routinely synthesized [18F]FCH by a modified 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) synthesizer (GE TracerLab MX). The radiosynthesis of [18F]FCH was completed in two steps taking 49 min. First, [18F]fluorobromomethane ([18F]FCH2Br) was synthesized from [18F]fluoride and dibromethane. Then, [18F]FCH as bromide salt was produced by N-alkylation of N,N-dimethylaminoethanol (DMAE) with [18F]fluorobromomethane. [18F]FCH had > 99.99% radiochemical purity, with non-decay-corrected and decay-corrected yields of 12(± 3)% and 16(± 4)%, respectively (n = 8). [ABSTRACT FROM AUTHOR]

In the last decade, microfluidic techniques have been explored in radiochemistry, and some of them have been implemented in preclinical production. However, these are not suitable and reliable for preparing different types of radiotracers or dose-on-demand production. A fully automated iMiDEV™ microfluidic radiosynthesizer has been introduced and this study is aimed at using of the iMiDEV™ radiosynthesizer with a microfluidic cassette to produce [11C]flumazenil and [11C]L-deprenyl. These two are known PET radioligands for benzodiazepine receptors and monoamine oxidase-B (MAO-B), respectively. Methods were successfully developed to produce [11C]flumazenil and [11C]L-deprenyl using [11C]methyl iodide and [11C]methyl triflate, respectively. The final products 1644 ± 504 MBq (n = 7) and 533 ± 20 MBq (n = 3) of [11C]flumazenil and [11C]L-deprenyl were produced with radiochemical purities were over 98% and the molar activity for [11C]flumazenil and [11C]L-deprenyl was 1912 ± 552 GBq/µmol, and 1463 ± 439 GBq/µmol, respectively, at the end of synthesis. All the QC tests complied with the European Pharmacopeia. Different parameters, such as solvents, bases, methylating agents, precursor concentration, and different batches of cassettes, were explored to increase the radiochemical yield. Synthesis methods were developed using 3–5 times less precursor than conventional methods. The fully automated iMiDEV™ microfluidic radiosynthesizer was successfully applied to prepare [11C]flumazenil and [11C]L-deprenyl. [ABSTRACT FROM AUTHOR]

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In order to accommodate the growing demand for positron emission tomography (PET), it will be necessary to create innovative radiochemical and engineering technologies to optimize the manufacture and development of PET probes. Microfluidic devices allow radiosynthesis to be performed in microscale amounts, significantly impacting PET tracer production. Compared to traditional methods, microfluidic devices can produce PET tracers in a shorter time, higher yields, with lower reagent consumption, higher molar activity, and faster purification. This review examines microfluidic devices from an engineering perspective. Recently developed microfluidic radiosynthesis devices are classified into three categories according to their reaction volume: continuous‐flow, batch‐flow, and droplet‐based microreactors. The principles of device architecture, radiosynthesis process, and the relative strengths and limitations of each category are emphasized by citing typical examples. Finally, the possible future applications of this technology are outlined. A flexible, miniature, fully automated radiochemical microfluidic platform will offer more straightforward and cheaper molecular imaging procedures and the potential for precision medicine that could allow operators to create customized tracers for individual patient doses. [ABSTRACT FROM AUTHOR]

In this concise practitioner protocol, the radiochemical synthesis of 2′‐deoxy‐2′‐[18F]fluoro‐9‐β‐d‐arabinofuranosylguanine ([18F]FAraG) suitable for human positron emission tomography (PET) studies is described and the results from validation productions are presented. The high specific activity (sometimes referred to as molar activity) radiotracer product is prepared as a sterile, apyrogenic solution that conforms to current Good Manufacturing Practice (cGMP) requirements established by the U.S. Food and Drug Administration. [ABSTRACT FROM AUTHOR]

Background: Antimicrobial peptides (AMPs) such as UBI-29-41 offer a distinctive approach for precise detection due to their unique interactions with bacteria and makes them promising candidates for specific and selective imaging. The study was aimed to corroborate the in-house manual synthesis of 68 Ga-NOTA-UBI-29-41, evaluate its uptake in patients with suspected infection, and estimate of patient-specific dosimetry to ensure optimal clinical application. Materials and Methods: 68 Ga-NOTA-UBI-29-41 was synthesized by using a variable amount of UBI-29-41 (60-90 μg) to 555 MBq of Ga-68 in 0.05 M Hydrochloric acid (HCl) and heating the reaction sample for 12 min at 90°C at pH: 3.5-4 to obtain the radiopeptide with high yield and high radiochemical purity (RCP). 68 Ga-NOTA-UBI-29-41 positron emission tomography/Computed tomography (CT) scans at variable timepoints were done to evaluate its biodistribution and maximum uptake time. Furthermore, patient-specific dosimetric estimation was done using the HERMES software. Results: A total of 5 μg/37 MBq (5 μg/mCi) of NOTA-UBI-29-41 for 12 min at 90°C were the optimal parameters to obtain 88%-90% of yield and 98%-99 % of RCP. 68 Ga-NOTA-UBI-29-41 showed expeditious blood clearance and high renal excretion. The optimal time for imaging of infection with 68 Ga-NOTA-UBI-29-41 was found to be at 60 min postinjection ( n = 8). The critical organ was the urinary bladder, receiving an average dose of 138.02 ± 45.92 µSv/MBq, followed by 53.81 ± 13.72 µSv/MBq for kidneys with a mean effective dose of 1.52 ± 0.64 mSv. Conclusion: The protocol for in-house manual labeling of 68 Ga-NOTA-UBI-29-41 was reproducible, providing high yield and RCP. 68 Ga-NOTA-UBI-29-41 administration was found to be safe and nontoxic. The favorable biodistribution and the first-in-human patient-specific dosimetry ensure optimal clinical application.

[18F]PARPi is currently undergoing clinical trials as a PET tracer for many applications. However, only manual radiosynthesis was reported; this has several drawbacks, including an increased risk of contamination from the operator, and the need to limit the starting activity. The automation of the previously reported protocol for [18F]PARPi synthesis is challenging, as it requires transferring microvolumes of reagents, which many platforms cannot accommodate. We report a revised, high yield, and automated protocol for the radiosynthesis of [18F]PARPi, with final doses of over 20 GBq. [ABSTRACT FROM AUTHOR]

6-[18F]fluoro-L-DOPA is a radiotracer widely used in the diagnosis of a range of diseases, including neuro-oncology, endocrinology, and Parkinson's disease. To meet the rapidly growing clinical need for this radioactive compound, this study reports an optimized radiosynthesis for this molecule, which proved to be highly reliable and compatible with different types of automated radiosynthesizers. Moreover, with 6-[18F]fluoro-L-DOPA, the PET/CT imaging of a total of 23 patients has been conducted, further demonstrating this radiotracer as a clinically valuable reagent to diagnose congenital hyperinsulinism (CHI) of infants in a non-invasive manner and, more importantly, localize the exact lesion on pancreas. [ABSTRACT FROM AUTHOR]

[11 C]Carfentanil ([11 C]CFN) is a selective radiotracer for in vivo positron emission tomography imaging studies of the μ-opioid system that, in our laboratories, is synthesized by methylation of the corresponding carboxylate precursor with [11 C]MeOTf, and purified using a C2 solid-phase extraction cartridge. Changes in the commercial availability of common C2 cartridges have necessitated future proofing the synthesis of [11 C]CFN to maintain reliable delivery of the radiotracer for clinical imaging studies. An updated synthesis of [11 C]CFN is reported that replaces a now obsolete purification cartridge with a new commercially available version and also substitutes the organic solvents used in traditional production methods with ethanol.

Abstract Background The radiofluorinated levodopa analogue 6-[18F]F-l-DOPA (3,4-dihydroxy-6-18F-l-phenylalanine) is a commonly employed radiotracer for PET/CT imaging of multiple oncological and neurological indications. An unusually large number of different radiosyntheses have been published to the point where two different Ph. Eur. monographs exist depending on whether the chemistry relies on electrophilic or nucleophilic radiosubstitution of appropriate chemical precursors. For new PET imaging sites wishing to adopt [18F]FDOPA into clinical practice, selecting the appropriate production process may be difficult and dependent on the clinical needs of the site. Methods Data from four years of [18F]FDOPA production at three different clinical sites are collected and compared. These three sites, Aarhus University Hospital (AUH), Odense University Hospital (OUH), and Herlev University Hospital (HUH), produce the radiotracer by different radiosynthetic routes with AUH adopting an electrophilic strategy, while OUH and HUH employ two different nucleophilic approaches. Production failure rates, radiochemical yields, and molar activities are compared across sites and time. Additionally, the clinical use of the radiotracer over the time period considered at the different sites are presented and discussed. Results The electrophilic substitution route suffers from being demanding in terms of cyclotron operation and maintenance. This challenge, however, was found to be compensated by a production failure rate significantly below that of both nucleophilic approaches; a result of simpler chemistry. The five-step nucleophilic approach employed at HUH produces superior radiochemical yields compared to the three-step approach adopted at OUH but suffers from the need for more comprehensive synthesis equipment given the multi-step nature of the procedure, including HPLC purification. While the procedure at OUH furnishes the lowest radiochemical yield of the synthetic routes considered, it produces the highest molar activity. This is of importance across the clinical applications of the tracer discussed here, including dopamine synthesis in striatum of subjects with schizophrenia and congenital hyperinsulinism in infants. Conclusion For most sites either of the two nucleophilic substitution strategies should be favored. However, which of the two will depend on whether a given site wishes to optimize the radiochemical yield or the ease of the use.

[18F]FLUDA is a selective radiotracer for in vivo imaging of the adenosine A2A receptor (A2AR) 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: The fibroblast activation protein (FAP) is an emerging target for molecular imaging and therapy in cancer. OncoFAP is a novel small organic ligand for FAP with very high affinity. In this translational study, we establish [68Ga]Ga-OncoFAP-DOTAGA (68Ga-OncoFAP) radiolabeling, benchmark its properties in preclinical imaging, and evaluate its application in clinical PET scanning. Methods: 68Ga-OncoFAP was synthesized in a cassette-based fully automated labeling module. Lipophilicity, affinity, and serum stability of 68Ga-OncoFAP were assessed by determining logD7.4, IC50 values, and radiochemical purity. 68Ga-OncoFAP tumor uptake and imaging properties were assessed in preclinical dynamic PET/MRI in murine subcutaneous tumor models. Finally, biodistribution and uptake in a variety of tumor types were analyzed in 12 patients based on individual clinical indications that received 163 ± 50 MBq 68Ga-OncoFAP combined with PET/CT and PET/MRI. Results: 68Ga-OncoFAP radiosynthesis was accomplished with high radiochemical yields. Affinity for FAP, lipophilicity, and stability of 68Ga-OncoFAP measured are ideally suited for PET imaging. PET and gamma counting–based biodistribution demonstrated beneficial tracer kinetics and high uptake in murine FAP-expressing tumor models with high tumor-to-blood ratios of 8.6 ± 5.1 at 1 h and 38.1 ± 33.1 at 3 h p.i. Clinical 68Ga-OncoFAP-PET/CT and PET/MRI demonstrated favorable biodistribution and kinetics with high and reliable uptake in primary cancers (SUVmax 12.3 ± 2.3), lymph nodes (SUVmax 9.7 ± 8.3), and distant metastases (SUVmax up to 20.0). Conclusion: Favorable radiochemical properties, rapid clearance from organs and soft tissues, and intense tumor uptake validate 68Ga-OncoFAP as a powerful alternative to currently available FAP tracers. [ABSTRACT FROM AUTHOR]

By adapting previously reported reaction conditions, [18F]FMISO was synthesized using a TracerLab FX‐FDG module in 31 min from no carrier added [18F]fluoride in 56% radiochemical yield. A novel and simple purification setup based on disposable cartridges was developed allowing the radiopharmaceutical to be obtained in high radiochemical purity (>99.5%) and with chemical impurities far below the Ph.Eur.'s thresholds. Moreover, the study pinpointed some shortcomings of the high‐performance liquid chromatography (HPLC) method reported in the dedicated Ph.Eur's monograph. [ABSTRACT FROM AUTHOR]

This article provides a brief overview of the 18F isotope production using the Cyclone-30 cyclotron and two liquid targets with the volume of 0.5 and 2.0 ml, water enriched with the 18O isotope was used as the target material. The obtained isotope was used for serial production of the [18F]FDG radiopharmaceutical and supply of this medicine to the operating PET centers in Almaty. The isotope was also used for experimental syntheses of [18F]PSMA-1007 and Na[18F]F to assess the possibility of implementation these medicines into the production and medical practice of the Republic of Kazakhstan. The need for the implementation of [18F]PSMA-1007 is associated with the problem of early diagnosis and control of prostate cancer treatment, and Na[18F]F - with the earliest possible detection of bone metastases in malignant tumors of various localization. This paper provides the average radiochemical yield and the main quality parameters for [18F]FDG, [18F]PSMA-1007 and Na[18F]F. This scientific and practical work allows us to evaluate the three-year production experience and the possibilities of fluorine production by reaction (p,n) on the cyclotron С-30, and also reflects the prospects of using fluorine in the development of new-generation radiopharmaceuticals for the diagnosis of oncological diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Fluorine labelled 8-((E)-4-fluoro-but-2-enyl)-3β-p-tolyl-8-aza-bicyclo[3.2.1]octane-2β-carboxylic acid methyl ester ([18F]LBT999) is a selective radioligand for the in vivo neuroimaging and quantification of the dopamine transporter by Positron Emission Tomography (PET). [18F]LBT999 was produced on a TRACERlab FXFN for the Phase I study but for Phase III and a potent industrial production transfer, production was also implemented on an AllinOne (AIO) system requiring a single use cassette. Both production methods are reported herein. Results Automation of [18F]LBT999 radiosynthesis on FXFN was carried out in 35% yield (decay-corrected) in 65 min (n = 16), with a radiochemical purity higher than 99% and a molar activity of 158 GBq/μmol at the end of synthesis. The transfer to the AIO platform followed by optimizations allowed the production of [18F]LBT999 in 32.7% yield (decay-corrected) within 48 min (n = 5), with a radiochemical purity better than 98% and a molar activity above 154 GBq/μmol on average at the end of synthesis. Quality controls of both methods met the specification for clinical application. Conclusion Both modules allow efficient and reproducible radiosynthesis of [18F]LBT999 with good radiochemical yields and a reasonable synthesis time. The developments made on AIO, such as its ability to meet pharmaceutical criteria and to more easily comply with GMP requirements, make it an optimal approach for the potent industrial production of [18F]LBT999 and future wider use.

The histamine subtype 3 (H 3 ) receptor is an important drug target in the central nervous system (CNS), and PET imaging offers a promising technique for the noninvasive evaluation of CNS disease related to the H 3 receptor. In this study, we synthesized and evaluated the binding effects of [ 18 F]H3-2404 and [ 18 F]H3-2405 by modifying the structure of AZD5213, a selective H 3 antagonist. These two radioligands were prepared in high radiochemical yields and displayed stability in serum. The in vitro autoradiographic study in rat brain tissue and the following in vivo PET studies in mice demonstrated sufficient brain uptake but predominantly non-specific distribution in rodent brain. Although these data suggest that [ 18 F]H3-2404 and [ 18 F]H3-2405 are unsuitable as PET tracers for brain imaging of the H 3 receptor, this study provides a valuable attempt for optimizing 18 F labeled radiotracers based on AZD5213., (© 2024 Wiley-VCH GmbH.)

Gallium-68-labeled FAPI-46 has recently been proposed as a novel positron emission tomography imaging probe to diagnose and monitor a wide variety of cancers. Promising results from several ongoing clinical trials have led to a soaring demand for this radiotracer. Typical [ 68 Ga]Ga-FAPI-46 labeling protocols do not cope with multiple generator elutions, leaving radiopharmacies unable to scale-up the production and meet the demand. Here, we propose a robust and efficient automated radiosynthesis of [ 68 Ga]Ga-FAPI-46 on the Trasis miniAllinOne synthesizer, featuring a prepurification step which allows multiple generator elutions and ensures compatibility with a wide range of gallium-68 generators. Our approach was to optimize the prepurification step by first testing five different cationic cartridge chemistries. Only the strong cationic exchange (SCX) cartridges tested had sufficient affinities for quantitative trapping of >99.9%, while the weak cationics did not exceed 50%. Packaging, rinsing, or flowing of the selected SCX cartridges was not noticeable, but improvements in fluidics managed to save time. Based on our previous development experience of [ 68 Ga]Ga-FAPI-46, radiolabeling optimization was also carried out at different temperatures during 10 min. At temperatures above 100°C, radiochemical yield (RCY) > 80% was achieved without significantly increasing the chemical impurities (<5.5 μg mL -1 ). The optimized sequence was reproducibly conducted with three different brands of widely used generators (RCY >88%). A comparison with radiosyntheses carried out without prepurification steps was also conclusive in terms of RCY, radiochemical yield, and chemical purity. Finally, high-activity tests using elutions from three generators were also successful for these parameters. [ 68 Ga]Ga-FAPI-46 was consistently obtained in good radiochemical yields (>89%, n = 3 ), and the final product quality was compliant with internal specifications based on European Pharmacopoeia. This process is suitable for GMP production and allows scaling-up of routine productions, higher throughput, and, ultimately, better patient care., Competing Interests: Authors SD, CV, and TG were employed by Trasis. FV was employed by SOFIE iTheranostics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Paty, Degueldre, Provost, Schmitt, Trump, Fouque, Vriamont, Valla, Gendron and Madar.)