Positron Emission Tomography Radiopharmaceuticals Research Articles

The neuroinflammation signatures in different stages of the Alzheimer’s disease continuum

AbstractBackgroundThe natural history of Alzheimer’s disease (AD) comprises a long preclinical stage characterized by pathological changes that start decades before symptoms arise. Despite that AD is defined based on the presence of amyloid‐β (Aβ) and tau pathology, increasing evidence supports neuroinflammation as one of the earliest pathomechanistic alterations throughout the AD continuum. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. However, it remains unclear if there are patterns of spatial and temporal susceptibility to neuroinflammatory processes in the brain that may synergize with Aβ and tau accumulation, which drives neurodegeneration in a self‐reinforcing manner.MethodThis was a cross‐sectional study examining a total number of 283 subjects from the TRIAD cohort at McGill University Research Centre for Studies in Aging, Canada. Cerebral amyloid and tau neurofibrillary tangles were assessed using positron emission tomography (PET) radiopharmaceuticals [18F]AZD4694 ([18F]NAV4694) and [18F]MK6240 respectively. Cerebrospinal fluid (CSF) biomarkers including Aβ42, Aβ40, phosphorylated tau (p‐tau), total tau (t‐tau), neurofilament light (NfL), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), YKL40 and glial fibrillary acidic protein (GFAP) were also measured. Voxelwise analyses were performed to evaluate the relationships between cerebral amyloid load, tau burden and neuroinflammation biomarkers.ResultWe modelled biomarker changes as a function of amyloid PET standardized uptake value ratio (SUVR) and tau PET SUVR as proxies of disease progression. The earliest changes observed in the AD continuum were the decrease in the Aβ42/40 ratio and the increases in astrocytic biomarkers CSF YKL40 and CSF GFAP. This is followed by a steep increase in CSF pTau231 and, to a lesser extent, CSF pTau217 and CSF pTau181. Voxelwise analyses revealed that YKL40 and GFAP are associated with amyloid and tau load in the brain, after accounting for age, sex, education and pathological status.ConclusionNeuroinflammation involving astrocytic activation is altered very early in the Alzheimer’s continuum and could be targeted as a promising biomarker.

In silico development of new PET radiopharmaceuticals from mTOR inhibitors

Rapamycin (or sirolimus) is a macrolide that has shown to be useful as an immunosuppressant and that was studied in metabolic, neurological, or genetic disorders. Rapamycin is a specific natural inhibitor of the mechanistic target of rapamycin (mTOR) that is a kinase protein playing a pivotal role in cell growth and proliferation by activation of several metabolic processes. This work aimed to evaluate the utility of several compounds obtained from rapamycin and its semi-synthetic analogs everolimus and temsirolimus as possible radiopharmaceuticals oriented to this protein. Density Functional Theory calculations of these molecules were made and further analysis of the dual descriptor, charges populations, and of the electrostatic potential surfaces were performed. Molecular docking simulations were used to evaluate the interactions of the rapamycin with the studied candidates. They allowed us to propose two strategies for the synthesis of novel compounds based on electrophilic reactions. Molecular docking results also helped us to eliminate molecules that did not interact correctly with the target. Finally, we found for the first time, that the novel compounds synthesized through the electrophilic addition reaction that employed 18F-selectfluor, should maintain the biological activity of original compounds and could be suitable as Positron Emission Tomography radiopharmaceuticals targeting mTOR Complex1 system.

Sweetening Pharmaceutical Radiochemistry by 18F-Fluoroglycosylation: Recent Progress and Future Prospects.

In the field of 18F-chemistry for the development of radiopharmaceuticals for positron emission tomography (PET), various labeling strategies by the use of prosthetic groups have been implemented, including chemoselective 18F-labeling of biomolecules. Among those, chemoselective 18F-fluoroglycosylation methods focus on the sweetening of pharmaceutical radiochemistry by offering a highly valuable tool for the synthesis of 18F-glycoconjugates with suitable in vivo properties for PET imaging studies. A previous review covered the various 18F-fluoroglycosylation methods that were developed and applied as of 2014 (Maschauer and Prante, BioMed. Res. Int. 2014, 214748). This paper is an updated review, providing the recent progress in 18F-fluoroglycosylation reactions and the preclinical application of 18F-glycoconjugates, including small molecules, peptides, and high-molecular-weight proteins.

Assessment of occupational exposure from shielded and unshielded syringes for clinically relevant positron emission tomography (PET) isotopes—a Monte Carlo approach using EGSnrc

18F has been the most widely used radionuclide in positron emission tomography (PET) facilities over the last few decades. However, increased interest in novel PET tracers, theranostics and immuno-PET has led to significant growth in clinically used positron-emitting radionuclides. The decay schemes of each of these radioisotopes are markedly different from 18F, with different endpoint energies for the emitted positrons and, in some cases, additional high energy gamma radiation. This has implications for the occupational exposure of personnel involved in the manipulation and dispensing of PET radiopharmaceuticals. The EGSnrc Monte Carlo simulation software was used to estimate the doses to extremities in contact with unshielded and shielded syringes containing 64Cu, 18F, 11C, 13N, 15O, 68Ga and 89Zr, respectively. Dose rates at various distances from the syringe were also modelled, with dose rates reported in terms of eye (Hp(3)), skin equivalent (Hp(0.07)) and deep (Hp(10)) doses. The composition and geometry of the simulated syringe shields were based on a selection of commercially available PET shields. Experimental dose rate measurements were performed for validation purposes where possible. Contact skin dose rates for all isotopes, except for 64Cu, were found to be higher than 18F for the unshielded syringe. The addition of a shield resulted in approximately equal contact skin dose rates for nearly all isotopes, for each shield type, with the exception of 89Zr which was notably higher. Dose rate constants (µGy/MBq.hr) for a range of PET isotopes and shields are presented and their significance discussed.

Economical droplet-based microfluidic production of [18F]FET and [18F]Florbetaben suitable for human use

Current equipment and methods for preparation of radiopharmaceuticals for positron emission tomography (PET) are expensive and best suited for large-scale multi-doses batches. Microfluidic radiosynthesizers have been shown to provide an economic approach to synthesize these compounds in smaller quantities, but can also be scaled to clinically-relevant levels. Batch microfluidic approaches, in particular, offer significant reduction in system size and reagent consumption. Here we show a simple and rapid technique to concentrate the radioisotope, prior to synthesis in a droplet-based radiosynthesizer, enabling production of clinically-relevant batches of [18F]FET and [18F]FBB. The synthesis was carried out with an automated synthesizer platform based on a disposable Teflon-silicon surface-tension trap chip. Up to 0.1 mL (4 GBq) of radioactivity was used per synthesis by drying cyclotron-produced aqueous [18F]fluoride in small increments directly inside the reaction site. Precursor solution (10 µL) was added to the dried [18F]fluoride, the reaction chip was heated for 5 min to perform radiofluorination, and then a deprotection step was performed with addition of acid solution and heating. The product was recovered in 80 µL volume and transferred to analytical HPLC for purification. Purified product was formulated via evaporation and resuspension or a micro-SPE formulation system. Quality control testing was performed on 3 sequential batches of each tracer. The method afforded production of up to 0.8 GBq of [18F]FET and [18F]FBB. Each production was completed within an hour. All batches passed quality control testing, confirming suitability for human use. In summary, we present a simple and efficient synthesis of clinically-relevant batches of [18F]FET and [18F]FBB using a microfluidic radiosynthesizer. This work demonstrates that the droplet-based micro-radiosynthesizer has a potential for batch-on-demand synthesis of 18F-labeled radiopharmaceuticals for human use.

PET with Different Radiopharmaceuticals in Neuroendocrine Neoplasms: An Umbrella Review of Published Meta-Analyses.

Simple SummaryFunctional imaging methods and, in particular, positron emission tomography (PET) using several radiopharmaceuticals may play a pivotal role in patients with neuroendocrine neoplasms including neuroendocrine tumors (NETs) located in different sites, paraganglioma (PGL) and neuroblastoma (NB), recurrent medullary thyroid carcinoma (rMTC) and aggressive neuroendocrine neoplasms. Several radiopharmaceuticals can be used in this setting such as Gallium-68 somatostatin analogues (68Ga-SSA), Fluorine-18 fluorodihydroxyphenylalanine (18F-FDOPA), Gallium-68 exendin-4 (68Ga-exendin-4), Fluorine-18 fluorodeoxyglucose (18F-FDG). This umbrella review provides an evidence-based summary about meta-analyses on diagnostic performance, prognostic value, clinical impact and safety of PET with different radiopharmaceuticals in patients with neuroendocrine neoplasms. Overall, evidence-based data support the use of PET with different radiopharmaceuticals in patients with neuroendocrine neoplasms but with specific indications for each radiopharmaceutical.Background: Several meta-analyses have reported quantitative data about the diagnostic performance, the prognostic value, the impact on management and the safety of positron emission tomography (PET) including related hybrid modalities (PET/CT or PET/MRI) using different radiopharmaceuticals in patients with neuroendocrine neoplasms. We performed an umbrella review of published meta-analyses to provide an evidence-based summary. Methods: A comprehensive literature search of meta-analyses listed in PubMed/MEDLINE and Cochrane Library databases was carried out (last search date: 30 June 2021). Results: Thirty-four published meta-analyses were selected and summarized. About the diagnostic performance: 68Ga-SSA PET yields high diagnostic performance in patients with NETs and PGL; 18F-FDOPA PET yields good diagnostic performance in patients with intestinal NETs, PGL, NB, being the best available PET method in detecting rMTC; 68Ga-exendin-4 PET has good diagnostic accuracy in detecting insulinomas; 18F-FDG PET has good diagnostic performance in detecting aggressive neuroendocrine neoplasms. About the prognostic value: 68Ga-SSA PET has a recognized prognostic value in well-differentiated NETs, whereas 18F-FDG PET has a recognized prognostic value in aggressive neuroendocrine neoplasms. A significant clinical impact of 68Ga-SSA PET and related hybrid modalities in patients with NETs was demonstrated. There are no major toxicities or safety issues related to the use of PET radiopharmaceuticals in patients with neuroendocrine neoplasms. Conclusions: Evidence-based data support the use of PET with different radiopharmaceuticals in patients with neuroendocrine neoplasms with specific indications for each radiopharmaceutical.

A generic gas chromatography method for determination of residual solvents in PET radiopharmaceuticals

A novel gas chromatography (GC) method for quantitation of volatile organic compounds (VOCs) in 18F- and 11C-radiopharmaceuticals listed in the European Pharmacopoeia (Ph. Eur.) was proposed. Optimized chromatographic parameters were used for separation of ethanol, acetone, acetonitrile, tetrahydrofuran (THF), dibromomethane (DBM), 2-dimethylaminoethanol (deanol), N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) which could be detected in radioactive drug samples. The calculated peak resolutions (RS) were higher than 2.0 at ethanol concentration of up to 11 m/m%. Reproducible results could be obtained using base deactivated fused silica wool as packing material of inlet liner. Validation parameters showed excellent linearity (r2 ≥0.9998) in the range from 10 to at least 120% of concentration limit of solvents. The accuracy was determined as recovery of concentrations which ranged from 99.3% to 103.8%. Additionally, the relative standard deviation (RSD) of each solvent for inter-day and intra-day precision were in the range of 0.5–4.2% and 0.4–4.4%, respectively. The limit of quantitation (LOQ) for ethanol, acetone, acetonitrile, THF, DBM, deanol, DMF and DMSO was 0.48, 0.42, 0.43, 0.46, 4.35, 0.73, 0.68 and 0.50 mg/L, respectively. The developed procedure was successively applied for quantitation of ethanol, acetone, acetonitrile and deanol in radioactive drug samples of [11C]methionine, [11C]choline, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET). The proposed GC method applying flame ionization detection (FID) could be adapted in routine quality control of most frequently used positron emission tomography (PET) radiopharmaceuticals to perform the determination of residual solvents with analysis time of 12 min

Postmortem Neocortical 3H-PiB Binding and Levels of Unmodified and Pyroglutamate Aβ in Down Syndrome and Sporadic Alzheimer's Disease.

Individuals with Down syndrome (DS) have a genetic predisposition for amyloid-β (Aβ) overproduction and earlier onset of Aβ deposits compared to patients with sporadic late-onset Alzheimer’s disease (AD). Positron emission tomography (PET) with Pittsburgh Compound-B (PiB) detects fibrillar Aβ pathology in living people with DS and AD, but its relationship with heterogeneous Aβ forms aggregated within amyloid deposits is not well understood. We performed quantitative in vitro 3H-PiB binding assays and enzyme-linked immunosorbent assays of fibrillar (insoluble) unmodified Aβ40 and Aβ42 forms and N-terminus truncated and pyroglutamate-modified AβNpE3-40 and AβNpE3-42 forms in postmortem frontal cortex and precuneus samples from 18 DS cases aged 43–63 years and 17 late-onset AD cases aged 62–99 years. Both diagnostic groups had frequent neocortical neuritic plaques, while the DS group had more severe vascular amyloid pathology (cerebral amyloid angiopathy, CAA). Compared to the AD group, the DS group had higher levels of Aβ40 and AβNpE3-40, while the two groups did not differ by Aβ42 and AβNpE3-42 levels. This resulted in lower ratios of Aβ42/Aβ40 and AβNpE3-42/AβNpE3-40 in the DS group compared to the AD group. Correlations of Aβ42/Aβ40 and AβNpE3-42/AβNpE3-40 ratios with CAA severity were strong in DS cases and weak in AD cases. Pyroglutamate-modified Aβ levels were lower than unmodified Aβ levels in both diagnostic groups, but within group proportions of both pyroglutamate-modified Aβ forms relative to both unmodified Aβ forms were lower in the DS group but not in the AD group. The two diagnostic groups did not differ by 3H-PiB binding levels. These results demonstrate that compared to late-onset AD cases, adult DS individuals with similar severity of neocortical neuritic plaques and greater CAA pathology have a preponderance of both pyroglutamate-modified AβNpE3-40 and unmodified Aβ40 forms. Despite the distinct molecular profile of Aβ forms and greater vascular amyloidosis in DS cases, cortical 3H-PiB binding does not distinguish between diagnostic groups that are at an advanced level of amyloid plaque pathology. This underscores the need for the development of CAA-selective PET radiopharmaceuticals to detect and track the progression of cerebral vascular amyloid deposits in relation to Aβ plaques in individuals with DS.

Recent Advances in Photo-mediated Radiofluorination.

Carbon-fluorine bond formations have received a lot of attention because organofluorine compounds are widely used in pharmaceutical, agricultural, and materials science applications. In particular, the incorporation of fluorine-18, which is a commonly used radioisotope for radiopharmaceuticals for positron emission tomography (PET), a molecular imaging tool for the visualization of biochemical events, human metabolism processes, and the measurement and diagnosis of diseases in humans, plays a crucial role in clinical and preclinical studies. Several synthetic methodologies for carbon-fluorine-18 bond formation have been developed. However, conventional fluorination methods have some remaining drawbacks such as the high temperature and basic environment. Photo-induced catalysis is an emerging technique that allow chemists to achieve the synthesis of target molecular architectures under mild conditions. Moreover, several radiofluorination strategies have been developed via photocatalysis. In this review, we focused on describing recent advances in the field of light-mediated radiofluorination.

Two Novel PET Radiopharmaceuticals for Endothelial Vascular Cell Adhesion Molecule-1 (VCAM-1) Targeting.

Atherosclerosis is a chronic progressive disease involving inflammatory events, such as the overexpression of adhesion molecules including the endothelial Vascular Cell Adhesion Molecule-1 (VCAM-1). VCAM-1 is rapidly overexpressed in the first stages of atherosclerosis, thus representing a promising target for early atheroma detection. Two novel Positron Emission Tomography (PET) radiopharmaceuticals (MacroP and NAMP), based on the VCAM-1-binding peptide having sequence VHPKQHRGGSKGC, were synthesized and characterized. MacroP is derived from the direct conjugation of a DOTA derivative with the peptide, while NAMP is a biotin derivative conceived to be employed in a three-step pretargeting system, involving the use of a double-chelating derivative of DOTA. The identity of the newly synthesized radiopharmaceuticals was confirmed by mass spectrometry and, after radiolabeling with 68Ga, both showed high radiochemical purity; in vitro tests on human umbilical vein endothelial cells evidenced their VCAM-1 binding ability, with higher radioactive uptake in the case of NAMP. Moreover, NAMP might also be employed in a theranostic approach in association with functionalized biotinylated nanoparticles.

Progress in [18F]Fluorination by Using Aryliodonium(III) Compounds and Application for PET Tracer Syntheses

[18F]-labeled drugs and radioligands are most frequently used in positron-emission tomography (PET) radiopharmaceuticals for both clinical and preclinical research. Various methods for the introduction of [18F]fluorine into complex molecules through fluorination reactions have been reported. Herein, recent advances in [18F]-fluorination utilizing aryliodonium(III) compounds are highlighted.

Hybrid imaging of complicating osteomyelitis in the peripheral skeleton.

Diagnosing complicating osteomyelitis (COM) is clinically challenging. Laboratory tests are of limited utility, and other than isolation of the offending organism, diagnostic imaging tests are of paramount importance. Nuclear Medicine techniques play an important role in noninvasive evaluation of osteomyelitis, using both single-photon emission tomography (SPECT) and positron emission tomography (PET) radiopharmaceuticals. It is well-known that those conventional imaging modalities are not performing well in the distinction between soft-tissue and deep bone infection due to the lack of anatomical information. These difficulties have been overcome, to a great extent, with the introduction of in-line SPECT-CT and PET-CT systems which have revolutionized the field of diagnostic medical imaging. Hybrid imaging is especially useful in sites of suspected COM with underlying structural bone alterations. The first clinical studies with these integrated hybrid machines in the field of COM, including metallic implants imaging, are highly promising. In summary, WBC/AGA SPECT-CT and FDG-PET-CT seem to be the most accurate hybrid imaging modality for COM of the peripheral bone. However, there are still false positives, especially in aseptic tibial nonunions and/or metallic implants, as well as in the immediate postoperative setting. Furthermore, there is a lack of well-designed large multicentre prospective studies. Hopefully, in the future, the complementary use of morphological and functional hybrid imaging modalities may overcome some of the challenges faced in the assessment of COM.

A New, Second Generation Trithiol Bifunctional Chelate for 72,77As: Trithiol(b)-(Ser)2-RM2

Trithiol chelates are suitable for labeling radioarsenic (72As: 2.49 MeV β+, 26 h; 77As: 0.683 MeV β-, 38.8 h) to form potential theranostic radiopharmaceuticals for positron emission tomography (PET) imaging and therapy. A trithiol(b)-(Ser)2-RM2 bioconjugate and its arsenic complex were synthesized and characterized. The trithiol(b)-(Ser)2-RM2 bioconjugate was radiolabeled with no-carrier-added 77As in over 95% radiochemical yield and was stable for over 48 h, and in vitro IC50 cell binding studies of [77As]As-trithiol(b)-(Ser)2-RM2 in PC-3 cells demonstrated high affinity for the gastrin-releasing peptide (GRP) receptor (low nanomolar range). Limited biodistribution studies in normal mice were performed with HPLC purified 77As-trithiol(b)-(Ser)2-RM2 demonstrating both pancreatic uptake and hepatobiliary clearance.

68Ga-DOTATOC.

The radiopharmaceutical 68Ga-DOTATOC represents the latest radiopharmaceutical in the diagnosis of a neuroendocrine tumor with somatostatin receptor overexpression. Technological and economic difficulties of preparing and quality control of the radiopharmaceutical limit its use to specialised departments. Background of the department with rich experience with radiopharmaceuticals for positron emission tomography allows handling more difficult 68Ga-radiopharmacy and may increase and improve the care of oncology patients.

Thai National Guideline for Nuclear Medicine Investigations in Epilepsy.

Epilepsy is a disorder of the brain, which is characterized by recurrent epileptic seizures. These patients are generally treated with antiepileptic drugs. However, more than 30% of the patients become medically intractable and undergo a series of investigations to define candidates for epilepsy surgery. Nuclear Medicine studies using Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) radiopharmaceuticals are among the investigations used for this purpose. Since available guidelines for the investigation of surgical candidates are not up-to-date, The Nuclear Medicine Society of Thailand, The Neurological Society of Thailand, The Royal College of Neurological Surgeons of Thailand, and The Thai Medical Physicist Society has collaborated to develop this Thai national guideline for Nuclear Medicine study in epilepsy. The guideline focuses on the use of brain perfusion SPECT and F-18 fluorodeoxyglucose PET (FDG-PET), the mainly used methods in day-to-day practice. This guideline aims for effective use of Nuclear Medicine investigations by referring physicians e.g. epileptologists and neurologists, radiologists, nuclear medicine physicians, medical physicists, nuclear medicine technologists and technicians.

An Update on Extemporaneous Preparation of Radiopharmaceuticals Using Freeze-Dried Cold Kits.

The field of nuclear medicine is rapidly evolving due to the high demand of radiopharmaceuticals for diagnostic and therapeutic applications. The availability of a vast array of radioisotopes, improvement in radiolabeling strategies, and advancements in detection systems have also contributed to the progress in this field. Radiopharmaceuticals are mainly classified based on their application as diagnostic or therapeutic radiopharmaceuticals. These are available either as ready to use preparations or prepared at hospital radiopharmacy either using automated synthesis modules or by using freezedried cold kit formulations. Availability of freeze-dried cold kits for preparation of varied radiopharmaceuticals for targeting various organs and tumors played an essential role in the extensive use of 99mTc radiopharmaceuticals for diagnostic imaging by single-photon emission computed tomography (SPECT) imaging. Cold kits are especially suitable for the preparation of radiopharmaceuticals labeled with isotopes like 177Lu with relatively long half-life or radionuclides produced by radioisotope generators. A simplified procedure for the preparation of positron emission tomography (PET) radiopharmaceuticals is also desired to achieve images with higher resolution and sensitivity offered by PET. Robust kit formulations will simplify the preparation of PET radiopharmaceuticals and will contribute to extensive applications of positron emitters such as 68Ga. Several therapeutic radiopharmaceuticals are also being made using cold kits of the ligands. This review provides an update on diagnostic and therapeutic radiopharmaceuticals prepared using cold kits.

Procedural recommendations of cardiac PET/CT imaging: standardization in inflammatory-, infective-, infiltrative-, and innervation- (4Is) related cardiovascular diseases: a joint collaboration of the EACVI and the EANM:summary.

With this summarized document we share the standard for positron emission tomography (PET)/(diagnostic)computed tomography (CT) imaging procedures in cardiovascular diseases that are inflammatory, infective, infiltrative, or associated with dysfunctional innervation (4Is) as recently published in the European Journal of Nuclear Medicine and Molecular Imaging. This standard should be applied in clinical practice and integrated in clinical (multicentre) trials for optimal standardization of the procedurals and interpretations. A major focus is put on procedures using [18F]-2-fluoro-2-deoxyglucose ([18F]FDG), but 4Is PET radiopharmaceuticals beyond [18F]FDG are also described in this summarized document. Whilst these novel tracers are currently mainly applied in early clinical trials, some multicentre trials are underway and we foresee in the near future their use in clinical care and inclusion in the clinical guidelines. Diagnosis and management of 4Is related cardiovascular diseases are generally complex and often require a multidisciplinary approach by a team of experts. The new standards described herein should be applied when using PET/CT and PET/magnetic resonance, within a multimodality imaging framework both in clinical practice and in clinical trials for 4Is cardiovascular indications.

Development of PET Radiopharmaceuticals at the Tokyo Metropolitan Institute of Gerontology 2010-2019

Approximately 150 medical cyclotrons are installed in Japan for the production of conventional positron emission tomography (PET) radionuclides for routine nuclear medicine practice. The PET Center of Tokyo Metropolitan Institute of Gerontology (TMIG) was the 19th PET Center to be established in Japan. It has provided continuous service since 1990, performing basic and clinical studies as well as clinical diagnosis, and underwent an upgrade in 2013. It is clear that the novel PET radiopharmaceuticals can provide new tools for research and exploration of the PET-based diagnosis of various diseases. From this standpoint, we have undertaken the development of novel PET radiopharmaceuticals specifically for the investigation of brain function. The status of the development of the novel PET radiopharmaceuticals for clinical use at TMIG 2010-2019 is reviewed here.

19F- and 18F-Arene Deoxyfluorination via Organic Photoredox-Catalysed Polarity-Reversed Nucleophilic Aromatic Substitution.

Nucleophilic aromatic substitution (SNAr) is routinely used to install 19F− and 18F− in aromatic molecules, but is typically limited to electron-deficient arenes due to kinetic barriers associated with C–F bond formation. Here we demonstrate that a polarity-reversed photoredox-catalysed arene deoxyfluorination operating via cation radical-accelerated nucleophilic aromatic substitution (CRA-SNAr) enables the fluorination of electron-rich arenes with 19F− and 18F− under mild conditions, thus complementing the traditional arene polarity requirements necessary for SNAr-based fluorination. The utility of our radiofluorination strategy is highlighted by short reaction times, compatibility with multiple nucleofuges, and high radiofluorination yields, especially that of an important cancer positron emission tomography (PET) agent [18F]5-fluorouracil ([18F]FU). Taken together, our fluorination approach enables the development of fluorinated and radiofluorinated compounds that can be difficult to access by classical SNAr strategies, with the potential for use in the synthesis and discovery of PET radiopharmaceuticals.

Post-mortem analyses of PiB and flutemetamol in diffuse and cored amyloid-\u03b2 plaques in Alzheimer\u2019s disease

Specificity and sensitivity of positron emission tomography (PET) radiopharmaceuticals targeting fibrillar amyloid-β (Aβ) deposits is high for detection of neuritic Aβ plaques, a mature form of Aβ deposits which often have dense Aβ core (i.e., cored plaques). However, imaging-to-autopsy validation studies of amyloid PET radioligands have identified several false positive cases all of which had mainly diffuse Aβ plaques (i.e., plaques without neuritic pathology or dense amyloid core), and high amyloid PET signal was reported in the striatum where diffuse plaques predominate in Alzheimer’s disease (AD). Relative contributions of different plaque types to amyloid PET signal is unclear, particularly in neocortical areas where they are intermixed in AD. In vitro binding assay and autoradiography were performed using [3H]flutemetamol and [3H]Pittsburgh Compound-B (PiB) in frozen brain homogenates from 30 autopsy cases including sporadic AD and non-AD controls with a range of brain Aβ burden and plaque density. Fixed tissue sections of frontal cortex and caudate from 10 of the AD cases were processed for microscopy using fluorescent derivatives of flutemetamol (cyano-flutemetamol) and PiB (cyano-PiB) and compared to Aβ immunohistochemistry and pan-amyloid (X-34) histology. Using epifluorescence microscopy, percent area coverage and fluorescence output values of cyano-PiB- and cyano-flutemetamol-labeled plaques in two-dimensional microscopic fields were then calculated and combined to obtain integrated density measurements. Using confocal microscopy, we analysed total fluorescence output of the entire three-dimensional volume of individual cored plaques and diffuse plaques labeled with cyano-flutemetamol or cyano-PiB. [3H]Flutemetamol and [3H]PiB binding values in tissue homogenates correlated strongly and their binding pattern in tissue sections, as seen on autoradiograms, overlapped the pattern of Aβ-immunoreactive plaques on directly adjacent sections. Cyano-flutemetamol and cyano-PiB fluorescence was prominent in cored plaques and less so in diffuse plaques. Across brain regions and cases, percent area coverage of cyano-flutemetamol-labeled plaques correlated strongly with cyano-PiB-labeled and Aβ-immunoreactive plaques. For both ligands, plaque burden, calculated as percent area coverage of all Aβ plaque types, was similar in frontal cortex and caudate regions, while integrated density values were significantly greater in frontal cortex, which contained both cored plaques and diffuse plaques, compared to the caudate, which contained only diffuse plaques. Three-dimensional analysis of individual plaques labeled with either ligand showed that total fluorescence output of a single cored plaque was equivalent to total fluorescence output of approximately three diffuse plaques of similar volume. Our results indicate that [18F]flutemetamol and [11C]PiB PET signal is influenced by both diffuse plaques and cored plaques, and therefore is likely a function of plaque size and density of Aβ fibrils in plaques. Brain areas with large volumes/frequencies of diffuse plaques could yield [18F]flutemetamol and [11C]PiB PET retention levels comparable to brain regions with a lower volume/frequency of cored plaques.