Radiosynthesis and Preclinical Evaluation of -[F]FET and [F]FET-OMe as Novel [F]FET Analogs for Brain Tumor Imaging.

-([F]Fluoroethyl)-l-tyrosine ([F]FET) is actively transported into the brain and cancer cells by LAT1 and possibly other amino acid transporters, which enables brain tumor imaging by positron emission tomography (PET). However, tumor delivery of this probe in the presence of competing amino acids may be limited by a relatively low affinity for LAT1. The aim of the present work was to evaluate the -substituted [F]FET analog -[F]FET and the methyl ester [F]FET-OMe, which were designed to improve tumor delivery by altering the physicochemical, pharmacokinetic, and/or transport properties.

Desmethyl SuFEx-IT: SOF-Free Synthesis and Evaluation as a Fluorosulfurylating Agent.

Access to SuFExable compounds was remarkably simplified by introduction of the solid FOS-donor SuFEx-IT. However, the published process for preparation of this reagent relies on the use of sulfuryl fluoride (SOF), which is difficult to obtain and highly toxic. Herein, we disclose a simple protocol for SOF-free, hectogram-scale preparation of the analogous desmethyl SuFEx-IT from inexpensive starting materials.

Preparation of -Methyl-6-[F]fluoro- and 5-Hydroxy-7-[F]fluorotryptophans as Candidate PET-Tracers for Pathway-Specific Visualization of Tryptophan Metabolism.

Tryptophan (Trp) is an essential proteinogenic amino acid and metabolic precursor for several signaling molecules that has been implicated in many physiological and pathological processes. Since the two main branches of Trp metabolism-serotonin biosynthesis and kynurenine pathway-are differently affected by a variety of neurological and neoplastic diseases, selective visualization of these pathways is of high clinical relevance. However, while positron emission tomography (PET) with existing probes can be used for non-invasive assessment of total Trp metabolism, optimal imaging agents for pathway-specific PET imaging are still lacking.

Validation of analytical HPLC with post-column injection as a method for rapid and precise quantification of radiochemical yields.

Accurate assessment of isolated radiochemical yields (RCYs) is a prerequisite for efficient and reliable optimization of labeling reactions. In practice, radiochemical conversions (RCCs) determined by HPLC analysis of crude reaction mixtures are often used to estimate RCYs. However, incomplete recovery of radioactivity from the stationary phase can lead to significant inaccuracies if RCCs are calculated based on the activity eluted from the column (i.

7-[F]Fluoro-8-azaisatoic Anhydrides: Versatile Prosthetic Groups for the Preparation of PET Tracers.

F-Fluorination of sensitive molecules is often challenging, but can be accomplished under suitably mild conditions using radiofluorinated prosthetic groups (PGs). Herein, 1-alkylamino-7-[F]fluoro-8-azaisatoic anhydrides ([F]AFAs) are introduced as versatile F-labeled building blocks that can be used as amine-reactive or "click chemistry" PGs. [F]AFAs were efficiently prepared within 15 min by "on cartridge" radiolabeling of readily accessible trimethylammonium precursors.

Mutated Isocitrate Dehydrogenase (mIDH) as Target for PET Imaging in Gliomas.

Gliomas are the most common primary brain tumors in adults. A diffuse infiltrative growth pattern and high resistance to therapy make them largely incurable, but there are significant differences in the prognosis of patients with different subtypes of glioma. Mutations in isocitrate dehydrogenase (IDH) have been recognized as an important biomarker for glioma classification and a potential therapeutic target.

Next Generation Copper Mediators for the Efficient Production of F-Labeled Aromatics.

Cu-mediated radiofluorination is a versatile tool for the preparation of F-labeled (hetero)aromatics. In this work, we systematically evaluated a series of complexes and identified several generally applicable mediators for highly efficient radiofluorination of aryl boronic and stannyl substrates. Utilization of these mediators in nBuOH/DMI or DMI significantly improved F-labeling yields despite use of lower precursor amounts.

Convenient PET-tracer production via SuFEx F-fluorination of nanomolar precursor amounts.

Recently, a protocol for radiolabeling of aryl fluorosulfates ("SuFEx click radiolabeling") using ultrafast F/F isotopic exchange has been reported. Although promising, the original procedure turned out to be rather inefficient. However, systematic optimization of the reaction parameters allowed for development of a robust method for SuFEx radiolabeling which obviates the need for azeotropic drying, base addition and HPLC purification.

Assessment of the In Vivo Relationship Between Cerebral Hypometabolism, Tau Deposition, TSPO Expression, and Synaptic Density in a Tauopathy Mouse Model: a Multi-tracer PET Study.

Cerebral glucose hypometabolism is a typical hallmark of Alzheimer's disease (AD), usually associated with ongoing neurodegeneration and neuronal dysfunction. However, underlying pathological processes are not fully understood and reproducibility in animal models is not well established. The aim of the present study was to investigate the regional interrelation of glucose hypometabolism measured by [F]FDG positron emission tomography (PET) with various molecular targets of AD pathophysiology using the PET tracers [F]PI-2620 for tau deposition, [F]DPA-714 for TSPO expression associated with neuroinflammation, and [F]UCB-H for synaptic density in a transgenic tauopathy mouse model.

Imaging of cerebral tryptophan metabolism using 7-[F]FTrp-PET in a unilateral Parkinsonian rat model.

Degradation products of the essential amino acid tryptophan (Trp) are important signaling molecules in the mammalian brain. Trp is metabolized either through the kynurenine pathway or enters serotonin and melatonin syntheses. The aim of the present work was to examine the potential of the novel PET tracer 7-[F]fluorotryptophan ([F]FTrp) to visualize all three pathways in a unilateral 6-OHDA rat model.

Evaluation of 3-l- and 3-d-[F]Fluorophenylalanines as PET Tracers for Tumor Imaging.

Purpose: The preclinical evaluation of 3-l- and 3-d-[F]FPhe in comparison to [F]FET, an established tracer for tumor imaging.

Methods: In vitro studies were conducted with MCF-7, PC-3, and U87 MG human tumor cell lines. In vivo µPET studies were conducted in healthy rats with/without the inhibition of peripheral aromatic l-amino acid decarboxylase by benserazide pretreatment ( = 3 each), in mice bearing subcutaneous MCF-7 or PC-3 tumor xenografts ( = 10), and in rats bearing orthotopic U87 MG tumor xenografts ( = 14).

Drug Penetration into the Central Nervous System: Pharmacokinetic Concepts and In Vitro Model Systems.

Delivery of most drugs into the central nervous system (CNS) is restricted by the blood-brain barrier (BBB), which remains a significant bottleneck for development of novel CNS-targeted therapeutics or molecular tracers for neuroimaging. Consistent failure to reliably predict drug efficiency based on single measures for the rate or extent of brain penetration has led to the emergence of a more holistic framework that integrates data from various in vivo, in situ and in vitro assays to obtain a comprehensive description of drug delivery to and distribution within the brain. Coupled with ongoing development of suitable in vitro BBB models, this integrated approach promises to reduce the incidence of costly late-stage failures in CNS drug development, and could help to overcome some of the technical, economic and ethical issues associated with in vivo studies in animal models.

Production of 6-l-[F]Fluoro--tyrosine in an Automated Synthesis Module for C-Labeling.

6-l-[F]Fluoro--tyrosine (6-l-[F]FMT) represents a valuable alternative to 6-l-[F]FDOPA which is conventionally used for the diagnosis and staging of Parkinson's disease. However, clinical applications of 6-l-[F]FMT have been limited by the paucity of practical production methods for its automated production. Herein we describe the practical preparation of 6-l-[F]FMT using alcohol-enhanced Cu-mediated radiofluorination of Bpin-substituted chiral Ni(II) complex in the presence of non-basic BuONTf using a volatile PrOH/MeCN mixture as reaction solvent.

[F]ALX5406: A Brain-Penetrating Prodrug for GlyT1-Specific PET Imaging.

Selective inhibition of glycine transporter 1 (GlyT1) has emerged as a potential approach to alleviate -methyl-d-aspartate receptor (NMDAR) hypofunction in patients with schizophrenia and cognitive decline. ALX5407 is a potent and selective inhibitor of GlyT1 derived from the metabolic intermediate sarcosine (-methylglycine) that showed antipsychotic potential in a number of animal models. Whereas clinical application of ALX5407 is limited by adverse effects on motor performance and respiratory function, a suitably radiolabeled drug could represent a promising PET tracer for the visualization of GlyT1 in the brain.

Rapid F-labeling via Pd-catalyzed S-arylation in aqueous medium.

We report radiolabeling of thiol-containing substrates via Pd-catalyzed S-arylation with 2-[F]fluoro-5-iodopyridine, which is readily accessible using the "minimalist" radiofluorination method. The practicality of the procedure was confirmed by preparation of a novel PSMA-specific PET-tracer as well as labeling of glutathione, Aβ oligomer-binding RD2 peptide, bovine serum albumin and PSMA I&S.

Nuclear Medicine in Times of COVID-19: How Radiopharmaceuticals Could Help to Fight the Current and Future Pandemics.

The emergence and global spread of COVID-19, an infectious disease caused by the novel coronavirus SARS-CoV-2, has resulted in a continuing pandemic threat to global health. Nuclear medicine techniques can be used for functional imaging of (patho)physiological processes at the cellular or molecular level and for treatment approaches based on targeted delivery of therapeutic radionuclides. Ongoing development of radiolabeling methods has significantly improved the accessibility of radiopharmaceuticals for in vivo molecular imaging or targeted radionuclide therapy, but their use for biosafety threats such as SARS-CoV-2 is restricted by the contagious nature of these agents.

[F]-JK-PSMA-7 PET/CT Under Androgen Deprivation Therapy in Advanced Prostate Cancer.

Purpose: PSMA imaging is frequently used for monitoring of androgen deprivation therapy (ADT) in prostate cancer. In a previous study, [F]-JK-PSMA-7 exhibited favorable properties for tumor localization after biochemical recurrence. In this retrospective study, we evaluated the performance of [F]-JK-PSMA-7 under ADT.

Preparation of labeled aromatic amino acids via late-stage F-fluorination of chiral nickel and copper complexes.

A general protocol for the preparation of 18F-labeled AAAs and α-methyl-AAAs applying alcohol-enhanced Cu-mediated radiofluorination of Bpin-substituted chiral complexes using Ni/Cu-BPX templates as double protecting groups is reported. The chiral auxiliaries are easily accessible from commercially available starting materials in a few synthetic steps. The versatility of the method was demonstrated by the high-yielding preparation of a series of [18F]F-AAAs and the successful implementation of the protocol into automated radiosynthesis modules.

Preparation of a First F-Labeled Agonist for M Muscarinic Acetylcholine Receptors.

M muscarinic acetylcholine receptors (mAChRs) are abundant in postsynaptic nerve terminals of all forebrain regions and have been implicated in the cognitive decline associated with Alzheimer's disease and other CNS pathologies. Consequently, major efforts have been spent in the development of subtype-selective positron emission tomography (PET) tracers for mAChRs resulting in the development of several C-labeled probes. However, protocols for the preparation of F-labeled mAChR-ligands have not been published so far.

Positron Emission Tomography Imaging of Long-Term Expression of the 18 kDa Translocator Protein After Sudden Cardiac Arrest in Rats.

Background: Knowledge about the neuroinflammatory state during months after sudden cardiac arrest is scarce. Neuroinflammation is mediated by cells that express the 18 kDa translocator protein (TSPO). We determined the time course of TSPO-expressing cells in a rat model of sudden cardiac arrest using longitudinal in vivo positron emission tomography (PET) imaging with the TSPO-specific tracer [18F]DAA1106 over a period of 6 months.

Intraindividual Comparison of F-PSMA-1007 with Renally Excreted PSMA Ligands for PSMA PET Imaging in Patients with Relapsed Prostate Cancer.

F-prostate-specific membrane antigen (PSMA)-1007 is excreted mainly through the liver. We benchmarked the performance of F-PSMA-1007 against 3 renally excreted PSMA tracers. Among 668 patients, we selected 27 in whom PET/CT results obtained with Ga-PSMA-11, F-DCFPyL (2-(3-(1-carboxy-5-[(6-[F]fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid), or F-JK-PSMA-7 (JK, Juelich-Koeln) were interpreted as equivocal or negative or as oligometastatic disease (PET-1).

Alcohol-Supported Cu-Mediated F-Fluorination of Iodonium Salts under "Minimalist" Conditions.

In the era of personalized precision medicine, positron emission tomography (PET) and related hybrid methods like PET/CT and PET/MRI gain recognition as indispensable tools of clinical diagnostics. A broader implementation of these imaging modalities in clinical routine is closely dependent on the increased availability of established and emerging PET-tracers, which in turn could be accessible by the development of simple, reliable, and efficient radiolabeling procedures. A further requirement is a GMP production of imaging probes in automated synthesis modules.

Biodistribution and radiation dosimetry of [F]-JK-PSMA-7 as a novel prostate-specific membrane antigen-specific ligand for PET/CT imaging of prostate cancer.

Aim: We investigated the whole-body distribution and the radiation dosimetry of [F]-JK-PSMA-7, a novel F-labeled PSMA-ligand for PET/CT imaging of prostate cancer.

Methods: Ten patients with prostate cancer and biochemical recurrence or radiologic evidence of metastatic diseases were examined with 329-384 MBq (mean 359 ± 17 MBq) [F]-JK-PSMA-7. Eight sequential positron emission tomography (PET) scans were acquired from 20 min to 3 h after injection with IRB approval.

An F-Labeled PSMA Ligand for PET/CT of Prostate Cancer: First-in-Humans Observational Study and Clinical Experience with F-JK-PSMA-7 During the First Year of Application.

In preclinical trials, the recently developed tracer 2-methoxy-F-DCFPyL (F-JK-prostate-specific membrane antigen [PSMA]-7) has shown favorable properties regarding clinical performance and radiochemical accessibility. The aim of this study was to evaluate the clinical utility of F-JK-PSMA-7 for PET/CT imaging of patients with prostate cancer. In an Institutional Review Board-approved pilot study, the initial clinical utility of PET/CT imaging with F-JK-PSMA-7 was directly compared with Ga-PSMA-11 PET/CT in a group of 10 patients with prostate cancer.

Peripheral ganglia in healthy rats as target structures for the evaluation of PSMA imaging agents.

Background: The recent implementation of PET with prostate specific membrane antigen (PSMA)-specific radiotracers into the clinical practice has resulted in the significant improvement of accuracy in the detection of prostate carcinoma (PCa). PSMA-expression in ganglia has been regarded as an important pitfall in prostate carcinoma-PET diagnostics but has not found any practical use for diagnosis or therapy.

Methods: We explored this phenomenon and demonstrated the applicability of peripheral ganglia in healthy rats as surrogates for small PSMA positive lesions for the preclinical evaluation of diagnostic PCa PET probes.