F-labeled aryl fluorides are widely used as radiotracers for positron emission tomography (PET) imaging. Aryl halides (ArX) are particularly attractive precursors to these radiotracers, as they are ...readily available, inexpensive, and stable. However, to date, the direct preparation of
F-aryl fluorides from aryl halides remains limited to S
Ar reactions between highly activated ArX substrates and K
F. This report describes an aryl halide radiofluorination reaction in which the C(
)-
F bond is formed via a copper-mediated pathway. Copper
-heterocyclic carbene complexes serve as mediators for this transformation, using aryl halide substrates with directing groups at the
position. This reaction is applied to the radiofluorination of electronically diverse aryl halide derivatives, including the bioactive molecules vismodegib and PH089.
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. All currently used FAPI rely on a linker–chelator complex attached to the ‘inhibitor’. We describe a new automated method of the direct attachment of the radioisotope to the inhibitor, resulting in a >50% MW reduction with the hope of an improved tumor-to-background ratio and tumor uptake. Methods: 18FFluroFAPI was developed from a Sn precursor. This allowed for subsequent automated radioflourination. We obtained the biodistribution of 18FFluroFAPI in rats, performed estimated human radiation dosimetry, and performed a 100× expected single dose toxicology analysis for eventual first-in-human experiments. Results: The synthesis of the Sn precursor for FluorFAPI and the automated synthesis of 18FFluroFAPI was demonstrated. 18FFluroFAPI had favorable estimated human radiation dosimetry, and demonstrated no adverse effects when injected at a dose of 100× that planned for 18FFluroFAPI. Conclusions: With the successful development of an automated synthesis of 18FFluroFAPI, first-in-human testing can be planned with the hope of an improved tumor-to-background performance compared to other FAPI agents.
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.
This report describes the development of a Zn(OTf)2‐mediated method for converting α‐tertiary haloamides to the corresponding fluorine‐18 labelled α‐tertiary fluoroamides with no‐carrier‐added ...18Ftetramethylammonium fluoride. 1,5,7‐Triazabicyclo4.4.0dec‐5‐ene is an essential additive for achieving high radiochemical conversion. Under the optimised conditions, radiofluorination proceeds at sterically hindered tertiary sites in high radiochemical conversions, yields, and purities. This method has been successfully automated and applied to access >200 mCi (>7.4 GBq) of several model radiofluorides. Mechanistic studies led to the development of a new, nucleophilic C−H radiofluorination process using N‐sulphonyloxyamide substrates.
A high‐yielding radiofluorination of unprotected α‐tertiary haloamides is described. This method provides a new strategy for radiochemists to install fluorine‐18 into sterically protected environments for positron emission tomography imaging. Preliminary mechanistic studies were leveraged to develop a novel C−H radiofluorination reaction of N‐sulphonyloxyamides.
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 (
F1), a radioligand for HD and its preclinical evaluation
(autoradiography of post-mortem HD brains) and
(rodent and non-human primate brain PET).
F1 was synthesized in a 4.1% RCY (decay corrected) and in an average molar activity of 16.5 ± 12.5 GBq/μmol (445 ± 339 Ci/mmol).
F1 penetrated the blood-brain barrier of both rodents and primates, and specific saturable binding in post-mortem brain slices was observed that correlated to
HTT aggregates identified by immunohistochemistry.
Purpose
Copper-mediated radiofluorination (CMRF) is emerging as the method of choice for the formation of aromatic C–
18
F bonds. This minireview examines proof-of-concept, preclinical, and in-human ...imaging studies of new and established imaging agents containing aromatic C–
18
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.
Methods
A comprehensive literature search from April 2014 onwards of the Web of Science and PubMed library databases was performed to find reports that utilize CMRF for the synthesis of fluorine-18 radiopharmaceuticals, and these represent the primary body of research discussed in this minireview. Select conference proceedings, previous reports describing alternative methods for the synthesis of imaging agents, and preceding fluorine-19 methodologies have also been included for discussion.
Conclusions
CMRF has significantly expanded the chemical space that is accessible to fluorine-18 radiolabeling with production methods that can meet the regulatory requirements for use in Nuclear Medicine. Furthermore, it has enabled novel and improved syntheses of radiopharmaceuticals and facilitated subsequent PET imaging studies. The rapid adoption of CMRF will undoubtedly continue to simplify the production of imaging agents and inspire the development of new radiofluorination methodologies.
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. We also highlight development of Tauvid, the first tau PET radiotracer approved by the US FDA for tau imaging in adult patients with cognitive impairment who are being evaluated for Alzheimer's disease.
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. A
F analog would address these shortcomings while retaining the ability to image cholesterol use. The goal of this study was to prepare and evaluate a
F analog of NP-59 to serve as a PET imaging agent for functional imaging of the adrenal glands based on cholesterol use. Previous attempts to prepare such an analog of NP-59 have proven elusive. Preclinical and clinical evaluation could be performed once the new fluorine analog of NP-59 production was established.
The recent development of a new reagent for fluorination along with an improved route to the NP-59 precursor allowed for the preparation of a fluorine analog of NP-59, FNP-59. The radiochemistry for the
F-radiolabeled
F-FNP-59 is described, and rodent radiation dosimetry studies and in vivo imaging in New Zealand rabbits was performed. After in vivo toxicity studies, an investigational new drug approval was obtained, and the first-in-humans images with dosimetry using the agent were acquired.
In vivo toxicity studies demonstrated that FNP-59 is safe for use at the intended dose. Biodistribution studies with
F-FNP-59 demonstrated a pharmacokinetic profile similar to that of NP-59 but with decreased radiation exposure. In vivo animal images demonstrated expected uptake in tissues that use cholesterol: gallbladder, liver, and adrenal glands. In this first-in-humans study, subjects had no adverse events and images demonstrated accumulation in target tissues (liver and adrenal glands). Manipulation of uptake was also demonstrated with patients who received cosyntropin, resulting in improved uptake.
F-FNP-59 provided higher resolution images, with lower radiation dose to the subjects. It has the potential to provide a noninvasive test for patients with adrenocortical diseases.
Radiochemical conversion is an important term to be included in the “Consensus nomenclature rules for radiopharmaceutical chemistry”. Radiochemical conversion should be used to define reaction ...efficiency by measuring the transformation of components in a crude reaction mixture at a given time, whereas radiochemical yield is better suited to define the efficiency of an entire reaction process including, for example, separation, isolation, filtration, and formulation.
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