A comparison of routine [Ga]Ga-PSMA-11 preparation using Locametz and Illuccix kits.

Background: Approval of Locametz and Illuccix kits for the manufacture of [Ga]Ga-PSMA-11 (gallium Ga68 gozetotide), a PET imaging agent for prostate cancer, as well as the corresponding therapeutic ([Lu]Lu-PSMA-617 Pluvicto), has led to a rapid increase in demand for [Ga]Ga-PSMA-11 PET imaging. Radiopharmaceutical manufacturers, using Ge/Ga generators, may decide to adopt Locametz and/or Illuccix kits, which requires a comparison to select the most suitable kit for day-to-day use. The objective of this article is to compare both kits and provide guidance for selecting one for routine use, as well as evaluate labeling consistency of both kits during routine production.

Towards a General Method for Using Cyclotron-Produced Ga68 to Manufacture Clinical and Research Ga68 Tracers.

The success of multiple nuclear medicine radiotherapeutics in treating cancer requires an increased supply of companion diagnostic imaging agents radiolabeled with gallium-68. Cyclotron production addresses the need for access to gallium-68 and has been validated for use with commercially produced sterile kits. For novel research tracers undergoing translational studies (IND or RDRC), developing and purchasing sterile kits is time- and cost-prohibitive.

Automated radiosynthesis and preclinical imaging of a novel [F]fluorolidocaine analogue sequential C-H radiolabelling.

The most prominent myocardial voltage-gated sodium channel, Na1.5, is a major drug target for treating cardiovascular disease. However, treatment determination and therapeutic development are complicated partly by an inadequate understanding of how the density of SCN5A, the gene that encodes Na1.

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.

Automated Radiosynthesis of [F]FluoFAPI and Its Dosimetry and Single Acute Dose Toxicological Evaluation.

Background: Cancer-associated fibroblasts have become a new target for therapy. Fibroblasts present within malignancies express the fibroblast activation protein (FAP). Inhibitors to FAP (FAPI) are small molecules recently developed as a theranostic agents for imaging and radiotherapy.

Room-Temperature Photochemical Copper-Mediated Fluorination of Aryl Iodides.

This report describes a method for the photochemical Cu-mediated fluorination of aryl iodides with AgF via putative aryl radical (Ar•) intermediates. It involves irradiating an aryl iodide with UVB light (λ = 313 nm) in the presence of a mixture of Cu and Cu salts and AgF. Under these conditions, fluorination proceeds at room temperature for substrates containing diverse substituents, including alkoxy and alkyl groups, ketones, esters, sulfonate esters, sulfonamides, and protected amines.

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.

3-[F]Fluoro--hydroxyphenethylguanidine (3-[F]pHPG) PET-A Novel Imaging Modality for Paraganglioma.

Context: Functional positron emission tomography (PET) imaging for the characterization of pheochromocytoma and paraganglioma (PCC/PGL) and for detection of metastases in malignant disease, offers valuable clinical insights that can significantly guide patient treatment.

Objective: This work aimed to evaluate a novel PET radiotracer, 3-[F]fluoro--hydroxyphenethylguanidine (3-[F]pHPG), a norepinephrine analogue, for its ability to localize PCC/PGL.

Methods: 3-[F]pHPG PET/CT whole-body scans were performed on 16 patients (8 male:8 female; mean age 47.

Evaluating immunotherapeutic outcomes in triple-negative breast cancer with a cholesterol radiotracer in mice.

Evaluating the response to immune checkpoint inhibitors (ICIs) remains an unmet challenge in triple-negative breast cancer (TNBC). The requirement for cholesterol in the activation and function of T cells led us to hypothesize that quantifying cellular accumulation of this molecule could distinguish successful from ineffective checkpoint immunotherapy. To analyze accumulation of cholesterol by T cells in the immune microenvironment of breast cancer, we leveraged the PET radiotracer, eFNP-59.

Improved purification of cyclotron [Ga]GaCl for the production of Ga radiopharmaceuticals.

Introduction: Increased demand for NetSpot and Illuccix as requirement to receive the respective Lutathera and Pluvicto radiotherapies, and monitor subsequent response to treatment, have reinforced the need to develop alternative ways of producing gallium-68 (Ga). Building on our efforts to produce Ga in a liquid target on a GE PETtrace, the goal of this work is to modify the current GE Gallium Chloride cassette using the FASTLab 2 synthesis module to produce [Ga]GaCl equivalent to a 1.85 GBq generator and demonstrate compatibility with FDA-approved kits for production of Ga-labeled radiopharmaceuticals.

Zinc-Mediated Radiosynthesis of Unprotected Fluorine-18 Labelled α-Tertiary Amides.

This report describes the development of a Zn(OTf) -mediated method for converting α-tertiary haloamides to the corresponding fluorine-18 labelled α-tertiary fluoroamides with no-carrier-added [ F]tetramethylammonium fluoride. 1,5,7-Triazabicyclo[4.4.

Tandem Iridium-Catalyzed C-H Borylation/Copper-Mediated Radiofluorination of Aromatic C-H Bonds with [F]TBAF.

Direct C-H functionalization of (hetero)aromatic C-H bonds with iridium-catalyzed borylation followed by copper-mediated radiofluorination of the in situ generated organoboronates affords fluorine-18 labeled aromatics in high radiochemical conversions and meta-selectivities. This protocol describes the benchtop reaction assembly of the C-H borylation and radiofluorination steps, which can be utilized for the fluorine-18 labeling of densely functionalized bioactive scaffolds.

Predicting efficacy of immunotherapy in mice with triple negative breast cancer using a cholesterol PET radiotracer.

Predicting the response to cancer immunotherapy remains an unmet challenge in triple-negative breast cancer (TNBC) and other malignancies. T cells, the major target of current checkpoint inhibitor immunotherapies, accumulate cholesterol during activation to support proliferation and signaling. The requirement of cholesterol for anti-tumor functions of T cells led us to hypothesize that quantifying cellular accumulation of this molecule could distinguish successful from ineffective checkpoint immunotherapy.

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.

Preparation and Evaluation of Cu-Radiolabled Dual-Ligand Multifunctional Gold Nanoparticles for Tumor Theragnosis.

Gold nanoparticles (AuNPs) are cutting-edge platforms for combined diagnostic and therapeutic approaches due to their exquisite physicochemical and optical properties. Using the AuNPs physically produced by femtosecond pulsed laser ablation of bulk Au in deionized water, with a capping agent-free surface, the conjugation of functional ligands onto the AuNPs can be tunable between 0% and 100% coverage. By taking advantage of this property, AuNPs functionalized by two different types of active targeting ligands with predetermined ratios were fabricated.

Classics in Neuroimaging: Untangling the Role of Tau in Neurodegenerative Disorders Using Positron Emission Tomography.

Imaging of misfolded proteins implicated in neurodegenerative disorders using positron emission tomography (PET) imaging has revolutionized dementia research. In this viewpoint, the development of radiotracers for tau PET is highlighted. We draw attention to key innovations that were essential to development of radiotracers for imaging tau, from early imaging agents, through the structure-activity relationship (SAR) studies required to minimize off-target binding of the newer probes in use today.

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.

Radiosynthesis and Evaluation of Four Positron Emission Tomography Tracer Candidates for Imaging of Melatonin Receptors.

Melatonin is a neurohormone that modulates several physiological functions in mammals through the activation of melatonin receptor type 1 and 2 (MT and MT). The melatonergic system is an emerging therapeutic target for new pharmacological interventions in the treatment of sleep and mood disorders; thus, imaging tools to further investigate its role in the brain are highly sought-after. We aimed to develop selective radiotracers for imaging of both MT and MT by positron emission tomography (PET).

Synthesis and Evaluation of a Fluorine-18 Radioligand for Imaging Huntingtin Aggregates by Positron Emission Tomographic Imaging.

Mutations in the huntingtin gene (HTT) triggers aggregation of huntingtin protein (HTT), which is the hallmark pathology of neurodegenerative Huntington's disease (HD). Development of a high affinity F radiotracer would enable the study of Huntington's disease pathology using a non-invasive imaging modality, positron emission tomography (PET) imaging. Herein, we report the first synthesis of fluorine-18 imaging agent, 6-(5-((5-(2,2-difluoro-2-(fluoro-F)ethoxy)pyridin-2-yl)methoxy)benzo[]oxazol-2-yl)-2-methylpyridazin-3(2)-one ([F]1), a radioligand for HD and its preclinical evaluation (autoradiography of post-mortem HD brains) and (rodent and non-human primate brain PET).

SAr Radiofluorination with In Situ Generated [F]Tetramethylammonium Fluoride.

This report describes a method for the nucleophilic radiofluorination of (hetero)aryl chlorides, (hetero)aryl triflates, and nitroarenes using a combination of [F]KF·K and MeNHCO for the in situ formation of a strongly nucleophilic fluorinating reagent (proposed to be [F]MeNF). This method is applied to 24 substrates bearing diverse functional groups, and it generates [F](hetero)aryl fluoride products in good to excellent radiochemical yields in the presence of ambient air/moisture. The reaction is applied to the preparation of F-labeled HQ-415 for potential (pre)clinical use.

Preclinical evaluation of (S)-[F]GE387, a novel 18-kDa translocator protein (TSPO) PET radioligand with low binding sensitivity to human polymorphism rs6971.

Purpose: Positron emission tomography (PET) studies with radioligands for 18-kDa translocator protein (TSPO) have been instrumental in increasing our understanding of the complex role neuroinflammation plays in disorders affecting the brain. However, (R)-[C]PK11195, the first and most widely used TSPO radioligand has limitations, while the next-generation TSPO radioligands have suffered from high interindividual variability in binding due to a genetic polymorphism in the TSPO gene (rs6971). Herein, we present the biological evaluation of the two enantiomers of [F]GE387, which we have previously shown to have low sensitivity to this polymorphism.

Sequential Ir/Cu-Mediated Method for the -Selective C-H Radiofluorination of (Hetero)Arenes.

This article describes a sequential Ir/Cu-mediated process for the selective C-H radiofluorination of (hetero)arene substrates. In the first step, Ir-catalyzed C(sp)-H borylation affords (hetero)aryl pinacolboronate (BPin) esters. The intermediate organoboronates are then directly subjected to copper-mediated radiofluorination with [F]tetrabutylammonium fluoride to afford fluorine-18 labeled (hetero)arenes in high radiochemical yield and radiochemical purity.

Copper-Mediated Late-stage Radiofluorination: Five Years of Impact on Pre-clinical and Clinical PET Imaging.

Purpose: Copper-mediated radiofluorination (CMRF) is emerging as the method of choice for the formation of aromatic C-F bonds. This minireview examines proof-of-concept, pre-clinical, and in-human imaging studies of new and established imaging agents containing aromatic C-F bonds synthesized with CMRF. An exhaustive discussion of CMRF methods is not provided, although key developments that have enabled or improved upon the syntheses of fluorine-18 imaging agents are discussed.