3AcFNP-59 for Positron Emission Tomography Imaging of Cholesterol Trafficking and Utilization.

Cholesteryl ester analogues of [F]FNP-59 have the ability to provide information on cholesterol trafficking and utilization at earlier time points than those of [F]FNP-59 or [I]NP-59. It is well-known that free cholesterol and cholesteryl esters have differing distribution profiles and that they can be interconverted enzymatically. Substitution of the ester influences the rate of cholesterol ester hydrolysis and the subsequent mixing of cholesterol esters with the lipid pool in the body.

Improved Radiosynthesis and Automation of [C]2-(2,6-Difluoro-4-((2-(N-methylphenylsulfonamido)ethyl)thio)phenoxy)acetamide ([C]K2) for Positron Emission Tomography of the Glutamate α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid (AMPA) Receptor.

A new automated radiosynthesis of [C]2-(2,6-difluoro-4-((2-(N-methylphenylsulfonamido)ethyl)thio)phenoxy)acetamide ([C]K2), a radiopharmaceutical for the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, is reported. Although manual syntheses have been described, these are unsuitable for routine production of larger batches of [C]K2 for (pre)clinical PET imaging applications. To meet demands for the imaging agent from our functional neuroimaging collaborators, herein, we report a current good manufacturing practice (cGMP)-compliant synthesis of [C]K2 using a commercial synthesis module.

Automated production of C-labeled carboxylic acids and esters via "in-loop" C-carbonylation using GE FX synthesis modules.

An in-loop C-carbonylation process for the radiosynthesis of C-carboxylic acids and esters from halide precursors has been developed. The reaction proceeds at room temperature under mild conditions and enables C-carbonylation of both electron deficient and electron rich (hetero)aromatic halides to provide C-carboxylic acids and esters in good to excellent radiochemical yields, high radiochemical purity, and excellent molar activity. The process has been fully automated using commercial radiochemistry synthesis modules, and application to clinical production is demonstrated via validated cGMP radiosyntheses of [C]bexarotene and [C]acetoacetic acid.

Strategies for the Production of [C]LY2795050 for Clinical Use.

This report describes a comparison of four different routes for the clinical-scale radiosynthesis of the κ-opioid receptor antagonist [C]LY2795050. Palladium-mediated radiocyanation and radiocarbonylation of an aryl iodide precursor as well as copper-mediated radiocyanation of an aryl iodide and an aryl boronate ester have been investigated. Full automation of all four methods is reported, each of which provides [C]LY2795050 in sufficient radiochemical yield, molar activity, and radiochemical purity for clinical use.

Development of Fluorinated NP-59: A Revival of Cholesterol Use Imaging with PET.

Imaging of cholesterol use is possible with the I scintiscanning/SPECT agent NP-59. This agent provided a noninvasive measure of adrenal function and steroid synthesis. However, iodine isotopes resulted in poor resolution, manufacturing challenges, and high radiation dosimetry to patients that have limited their use and clinical impact.

Automated Synthesis of F-BCPP-EF {2--Butyl-4-Chloro-5-{6-[2-(2[F]fluoroethoxy)-Ethoxy]-Pyridin-3-ylmethoxy}-2-Pyridazin-3-One for Imaging of Mitochondrial Complex 1 in Parkinson's Disease.

Mitochondrial complex I (MC-I) is an essential component of brain bioenergetics and can be quantified and studied using positron emission tomography (PET). A specific high affinity F radiotracer for MC-I enables monitoring of neurodegenerative disease progression and pathology PET imaging. To facilitate clinical research studies tracking MC-I activity in Parkinson's disease and other neurodegenerative diseases, a fully automated synthesis of the recently described 2-butyl-4-chloro-5-{6-[2-(2[F]fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2-pyridazin-3-one ([F] BCPP-EF, ) was developed.

Synthesis of Ga-radiopharmaceuticals using both generator-derived and cyclotron-produced Ga as exemplified by [Ga]Ga-PSMA-11 for prostate cancer PET imaging.

[Ga]Ga-PSMA-11, a urea-based peptidomimetic, is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that targets the prostate-specific membrane antigen (PSMA). The recent Food and Drug Administration approval of [Ga]Ga-PSMA-11 for PET imaging of patients with prostate cancer, expected follow-up approval of companion radiotherapeutics (e.g.

An updated synthesis of N '-([ C]methyl)naltrindole for positron emission tomography imaging of the delta opioid receptor.

A new method for the synthesis of the highly selective delta opioid receptor (DOR) antagonist radiotracer N '-([ C]methyl)naltrindole ([ C]MeNTI) is described. The original synthesis required hydrogenation of a benzyl protecting group after C-labeling, which is challenging in modern radiochemistry laboratories that tend to be heavily automated and operate according to current good manufacturing practice. To address this challenge, we describe development of a novel MeNTI precursor bearing a methoxymethyl acetal (MOM) protecting group, which is easily removed with HCl, and employ it in an updated synthesis of [ C]MeNTI.

Cyclotron-based production of Ga, [Ga]GaCl, and [Ga]Ga-PSMA-11 from a liquid target.

Purpose: To optimize the direct production of Ga on a cyclotron, via the Zn(p,n)Ga reaction using a liquid cyclotron target. We Investigated the yield of cyclotron-produced Ga, extraction of [Ga]GaCl and subsequent [Ga]Ga-PSMA-11 labeling using an automated synthesis module.

Methods: Irradiations of a 1.

Use of 55 PET radiotracers under approval of a Radioactive Drug Research Committee (RDRC).

Background: In the US, EU and elsewhere, basic clinical research studies with positron emission tomography (PET) radiotracers that are generally recognized as safe and effective (GRASE) can often be conducted under institutional approval. For example, in the United States, such research is conducted under the oversight of a Radioactive Drug Research Committee (RDRC) as long as certain requirements are met. Firstly, the research must be for basic science and cannot be intended for immediate therapeutic or diagnostic purposes, or to determine the safety and effectiveness of the PET radiotracer.

Synthesis of high-molar-activity [F]6-fluoro-L-DOPA suitable for human use via Cu-mediated fluorination of a BPin precursor.

[F]6-fluoro-L-DOPA ([F]FDOPA) is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that is used to image Parkinson's disease, brain tumors, and focal hyperinsulinism of infancy. Despite these important applications, [F]FDOPA PET remains underutilized because of synthetic challenges associated with accessing the radiotracer for clinical use; these stem from the need to radiofluorinate a highly electron-rich catechol ring in the presence of an amino acid. To address this longstanding challenge in the PET radiochemistry community, we have developed a one-pot, two-step synthesis of high-molar-activity [F]FDOPA by Cu-mediated fluorination of a pinacol boronate (BPin) precursor.

The Effects of Intramuscular Naloxone Dose on Mu Receptor Displacement of Carfentanil in Rhesus Monkeys.

Naloxone (NLX) is a mu receptor antagonist used to treat acute opioid overdoses. Currently approved doses of naloxone to treat opioid overdoses are 4 mg intranasal (IN) and 2 mg intramuscular (IM). However, higher mu receptor occupancy (RO) may be required to treat overdoses due to more potent synthetic opioids such as fentanyl and carfentanil that have entered the illicit drug market recently.

Development and implementation of ISAR, a new synthesis platform for radiopharmaceutical production.

Background: PET radiopharmaceutical development and the implementation of a production method on a synthesis module is a complex and time-intensive task since new synthesis methods must be adapted to the confines of the synthesis platform in use. Commonly utilized single fluid bus architectures put multiple constraints on synthesis planning and execution, while conventional microfluidic solutions are limited by compatibility at the macro-to-micro interface. In this work we introduce the ISAR synthesis platform and custom-tailored fluid paths leveraging up to 70 individually addressable valves on a chip-based consumable.

One-pot synthesis of high molar activity 6-[F]fluoro-l-DOPA by Cu-mediated fluorination of a BPin precursor.

A one-pot two-step synthesis of 6-[F]fluoro-l-DOPA ([F]FDOPA) has been developed involving Cu-mediated radiofluorination of a pinacol boronate ester precursor. The method is fully automated, provides [F]FDOPA in good activity yield (104 ± 16 mCi, 6 ± 1%), excellent radiochemical purity (>99%) and high molar activity (3799 ± 2087 Ci mmol), n = 3, and has been validated to produce the radiotracer for human use.

Futureproofing [F]Fludeoxyglucose manufacture at an Academic Medical Center.

Background: We recently upgraded our [F]fludeoxyglucose (FDG) production capabilities with the goal of futureproofing our FDG clinical supply, expanding the number of batches of FDG we can manufacture each day, and improving patient throughput in our nuclear medicine clinic. In this paper we report upgrade of the synthesis modules to the GE FASTLab 2 platform (Phase 1) and cyclotron updates (Phase 2) from both practical and regulatory perspectives. We summarize our experience manufacturing FDG on the FASTLab 2 module with a high-yielding self-shielded niobium (Nb) fluorine-18 target.

Development of Positron Emission Tomography Radiotracers for the GABA Transporter 1.

In vivo positron emission tomography (PET) imaging of the γ-aminobutyric acid (GABA) receptor complex has been accomplished using radiolabeled benzodiazepine derivatives, but development of specific presynaptic radioligands targeting the neuronal membrane GABA transporter type 1 (GAT-1) has been less successful. The availability of new structure-activity studies of GAT-1 inhibitors and the introduction of a GAT-1 inhibitor (tiagabine, Gabatril) into clinical use prompted us to reinvestigate the syntheses of PET ligands for this transporter. Initial synthesis and rodent PET studies of N-[C]methylnipecotic acid confirmed the low brain uptake of that small and polar molecule.

An updated synthesis of [ C]carfentanil for positron emission tomography (PET) imaging of the μ-opioid receptor.

[ C]Carfentanil ([ 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 [ 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 [ C]CFN to maintain reliable delivery of the radiotracer for clinical imaging studies. An updated synthesis of [ 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.

An updated radiosynthesis of [F]AV1451 for tau PET imaging.

Background: [F]AV1451 is a commonly used radiotracer for imaging tau deposits in Alzheimer's disease (AD) and related non-AD tauopathies. Existing radiosyntheses of [F]AV1451 require complex purifications to provide doses suitable for use in clinical imaging studies. To address this issue, we have modified the synthesis of [F]AV1451 to use only 0.

A fully-automated one-pot synthesis of [18F]fluoromethylcholine with reduced dimethylaminoethanol contamination via [18F]fluoromethyl tosylate.

Introduction: A novel one-pot method for preparing [(18)F]fluoromethylcholine ([(18)F]FCH) via in situ generation of [(18)F]fluoromethyl tosylate ([(18)F]FCH2OTs), and subsequent [(18)F]fluoromethylation of dimethylaminoethanol (DMAE), has been developed.

Methods: [(18)F]FCH was prepared using a GE TRACERlab FXFN, although the method should be readily adaptable to any other fluorine-(18) synthesis module. Initially ditosylmethane was fluorinated to generate [(18)F]FCH2OTs.

Fully automated radiosynthesis of [¹¹C]PBR28, a radiopharmaceutical for the translocator protein (TSPO) 18 kDa, using a GE TRACERlab FXC-Pro.

In order to image the translocator protein (TSPO) 18kDa in the clinic using positron emission tomography (PET) imaging, we had a cause to prepare [(11)C]PBR28. In this communication we highlight our novel, recently developed, one-pot synthesis of the desmethyl-PBR28 precursor, as well as present an optimized fully automated preparation of [(11)C]PBR28 using a GE TRACERlab FX(C-Pro). Following radiolabelling, purification is achieved by HPLC and, to the best of our knowledge, the first reported example of reconstituting [(11)C]PBR28 into ethanolic saline using solid-phase extraction (SPE).

Highlighting the Versatility of the Tracerlab Synthesis Modules. Part 1: Fully Automated Production of [F]Labelled Radiopharmaceuticals using a Tracerlab FX(FN).

The field of radiochemistry is moving towards exclusive use of automated synthesis modules for production of clinical radiopharmaceutical doses. Such a move comes with many advantages, but also presents radiochemists with the challenge of re-configuring synthesis modules for production of radiopharmaceuticals that require non-conventional radiochemistry whilst maintaining full automation. This review showcases the versatility of the Tracerlab FX(FN) synthesis module by presenting simple, fully automated methods for producing [(18)F]FLT, [(18)F]FAZA, [(18)F]MPPF, [(18)F]FEOBV, [(18)F]sodium fluoride, [(18)F]fluorocholine and [(18)F]SFB.

Automated production of [11C]acetate and [11C]palmitate using a modified GE Tracerlab FX(C-Pro).

As researchers explore new applications for positron emission tomography radiopharmaceuticals, the demand for effective and readily available radiopharmaceuticals continues to increase. The syntheses of two such radiopharmaceuticals, [(11)C]acetate and [(11)C]palmitate, can be automated on the GE Tracerlab FX(C-Pro) by utilizing Grignard reactions. Radiochemical purities of the [(11)C]acetate and the [(11)C]palmitate products were high (>98% and >99.