Positron Emission Tomography Radiopharmaceuticals Research Articles

Titanium-45 (45Ti) Radiochemistry and Applications in Molecular Imaging.

Molecular imaging is an important part of modern medicine which enables the non-invasive identification and characterization of diseases. With the advancement of radiochemistry and scanner technology, nuclear medicine is providing insight into efficient treatment options for individual patients. Titanium-45 (45Ti) is a lesser-explored radionuclide that is garnering increasing interest for the development of positron emission tomography (PET) radiopharmaceuticals. This review discusses aspects of this radionuclide including production, purification, radiochemistry development, and molecular imaging studies.

Development of New CD38 Targeted Peptides for Cancer Imaging.

Multiple myeloma (MM) affects over 35,000 patients each year in the US. There remains a need for versatile Positron Emission Tomography (PET) tracers for the detection, accurate staging, and monitoring of treatment response of MM that have optimal specificity and translational attributes. CD38 is uniformly overexpressed in MM and thus represents an ideal target to develop CD38-targeted small molecule PET radiopharmaceuticals to address these challenges. Using phage display peptide libraries and pioneering algorithms, we identified novel CD38 specific peptides. Imaging bioconjugates were synthesized using solid phase peptide chemistry, and systematically analyzed in vitro and in vivo in relevant MM systems. The CD38-targetedbioconjugates were radiolabeled with copper-64 (64Cu) with100% radiochemical purity and an average specific activity of 3.3 - 6.6MBq/nmol. The analog NODAGA-PEG4-SL022-GGS (SL022: Thr-His-Tyr-Pro-Ile-Val-Ile) had a Kd of 7.55 ± 0.291nM and was chosen as the lead candidate. 64Cu-NODAGA-PEG4-SL022-GGS demonstrated high binding affinity to CD38 expressing human myeloma MM.1S-CBR-GFP-WT cells, which was blocked by the non-radiolabeled version of the peptide analog and anti-CD38 clinical antibodies, daratumumab and isatuximab, by 58%, 73%, and 78%, respectively. The CD38 positive MM.1S-CBR-GFP-WT cells had > 68% enhanced cellular binding when compared to MM.1S-CBR-GFP-KO cells devoid of CD38. Furthermore, our new CD38-targeted radiopharmaceutical allowed visualization of tumors located in marrow rich bones, remaining there for up to 4h. Clearance from non-target organs occurred within 60min. Quantitative PET data from a murine disseminated tumor model showed significantly higher accumulation in the bones of tumor-bearing animals compared to tumor-naïve animals (SUVmax 2.06 ± 0.4 versus 1.24 ± 0.4, P = 0.02). Independently, tumor uptake of the target compound was significantly higher (P = 0.003) compared to the scrambled peptide, 64Cu-NODAGA-PEG4-SL041-GGS (SL041: Thr-Tyr-His-Ile-Pro-Ile-Val). The subcutaneous MM model demonstrated significantly higher accumulation in tumors compared to muscle at 1 and 4h after tracer administration (SUVmax 0.8 ± 0.2 and 0.14 ± 0.04, P = 0.04 at 1h; SUVmax 0.89 ± 0.01 and 0.09 ± 0.01, P = 0.0002 at 4h). The novel CD38-targeted, radiolabeled bioconjugates were specific and allowed visualization of MM, providing a starting point for the clinical translation of such tracers for the detection of MM.

Radiochemistry and In Vivo Imaging of [45Ti]Ti-THP-PSMA.

Titanium-45 (45Ti) is a radionuclide with excellent physical characteristics for use in positron emission tomography (PET) imaging, including a moderate half-life (3.08 h), decay by positron emission (85%), and a low mean positron energy of 0.439 MeV. However, challenges associated with titanium chemistry have led to the underdevelopment of this radionuclide for incorporation into radiopharmaceuticals. Expanding on our recent studies, which showed promising results for the complexation of 45Ti with the tris hydroxypyridinone (THPMe) chelator, the current work aimed to optimize the chemistry and imaging attributes of [45Ti]Ti-THP-PSMA as a new PET radiopharmaceutical. Methods. Radiolabeling of THP-PSMA was optimized with [45Ti]Ti-citrate at varying pHs and masses of the precursor. The stability of the radiolabeled complex was assessed in mouse serum for up to 6 h. The affinity of [45Ti]Ti-THP-PSMA for prostate-specific membrane antigen (PSMA) was assessed using LNCaP (PSMA +) and PC3 (PSMA -) cell lines. In vivo imaging and biodistribution analysis were performed in tumor-bearing xenograft mouse models to confirm the specificity of the tumor uptake. Results. > 95% of radiolabeling was achieved with a high specific activity of 5.6 MBq/nmol under mild conditions. In vitro cell binding studies showed significant binding of the radiolabeled complex with the PSMA-expressing LNCaP cell line (11.9 ± 1.5%/mg protein-bound activity) compared to that with the nonexpressing PC3 cells (1.9 ± 0.4%/mg protein-bound activity). In vivo imaging and biodistribution studies confirmed specific uptake in LNCaP tumors (1.6 ± 0.27% ID/g) compared to that in PC3 tumors (0.39 ± 0.2% ID/g). Conclusion. This study showed a simple one-step radiolabeling method for 45Ti with THP-PSMA under mild conditions (pH 8 and 37 °C). In vitro cell studies showed promise, but in vivo tumor xenograft studies indicated low tumor uptake. Overall, this study shows the need for more chelators for 45Ti for the development of a PET radiopharmaceutical for cancer imaging.

Detection of Intestinal Inflammation by Vascular Adhesion Protein-1-Targeted [68Ga]Ga-DOTA-Siglec-9 Positron Emission Tomography in Murine Models of Inflammatory Bowel Disease

PurposeInflammatory bowel disease (IBD) can be imaged with positron emission tomography (PET), but existing PET radiopharmaceuticals have limited diagnostic accuracy. Vascular adhesion protein-1 (VAP-1) is an endothelial cell surface molecule that controls leukocyte extravasation into sites of inflammation. However, the role of inflammation-induced VAP-1 expression in IBD is still unclear. Therefore, this study investigated the utility of VAP-1-targeted [68Ga]Ga-DOTA-Siglec-9 positron emission tomography/computed tomography (PET/CT) for assessing inflammation in two mouse models of IBD.ProceduresStudies were performed using K8−/− mice that develop a chronic colitis-phenotype and C57Bl/6NCrl mice with acute intestinal inflammation chemically-induced using 2.5% dextran sodium sulfate (DSS) in drinking water. In both diseased and control mice, uptake of the VAP-1-targeting peptide [68Ga]Ga-DOTA-Siglec-9 was assessed in intestinal regions of interest using in vivo PET/CT, after which ex vivo gamma counting, digital autoradiography, and histopathological analyses were performed. Immunofluorescence staining was performed to determine VAP-1-expression in the intestine, including in samples from patients with ulcerative colitis.ResultsIntestinal inflammation could be visualized by [68Ga]Ga-DOTA-Siglec-9 PET/CT in two murine models of IBD. In both models, the in vivo PET/CT and ex vivo studies of [68Ga]Ga-DOTA-Siglec-9 uptake were significantly higher than in control mice. The in vivo uptake was increased on average 1.4-fold in the DSS model and 2.0-fold in the K8−/− model. Immunofluorescence staining revealed strong expression of VAP-1 in the inflamed intestines of both mice and patients.ConclusionsThis study suggests that the VAP-1-targeting [68Ga]Ga-DOTA-Siglec-9 PET tracer is a promising tool for non-invasive imaging of intestinal inflammation. Future studies in patients with IBD and evaluation of the potential value of [68Ga]Ga-DOTA-Siglec-9 in diagnosis and monitoring of the disease are warranted.

18F-labeled somatostatin analogs for somatostatin receptors (SSTRs) targeted PET imaging of neuroendocrine tumors (NETs)

A novel 18F-radiolabeled somatostatin analogue, [Al18F]NODA-MPAA-HTA, was synthesized and evaluated for positron emission tomography (PET) imaging of Neuroendocrine tumors (NETs). [Al18F]NODA-MPAA-HTA was designed and synthesized by conjugating 18F nuclide with a modified KE108 peptide, a somatostatin analog with high affinity for all five subtypes of somatostatin receptors (SSTR 1-5), through coupling a bifunctional chelator (NODA) to target somatostatin receptor (SSTR) positive tumors. The amino group of KE108 peptide, a SSTRs-targeting pharmacophore, was conjugated with the carboxyl group of NODA by a condensation reaction to obtain the labeling precursor of [Al18F]NODA-MPAA-HTA, in which its precursor was obtained through Fmoc solid-phase methods. A novel methodology for Al18F labeling of chelating agent-biomolecule conjugates was used to synthesize [Al18F]NODA-MPAA-HTA. In vitro stabilities of [Al18F]NODA-MPAA-HTA were evaluated by incubating it in saline or bovine serum for 2h. Ex vivo biodistribution and in vivo imaging of [Al18F]NODA-MPAA-HTA were further investigated to evaluate its SSTRs targeting ability and feasibility for the diagnosis of NETs using PET imaging. [Al18F]NODA-MPAA-HTA was synthesized using a one-step 18F-AlF labeling procedure resulting in moderate radiochemical yield (60-80%, non-decay corrected) and high radiochemical purity (>95%). It exhibited good hydrophilicity and excellent stability in vitro, with a molar activity of 122 GBq/μmol. At 30min and 60min, the uptake of [Al18F] NODA-MPAA-HTA by HEK293-SSTR2 cells was 5.47±0.97%/105 cells and 12.11±0.32%/105 cells, respectively. The affinity of [Al18F]NODA-MPAA-HTA for SSTR2 was determined to be 8.77±1.14nM. In micro-PET imaging of HEK293-SSTR2 tumor-bearing mice, [Al18F]NODA-MPAA-HTA showed high tumor uptake of radioactivity and a high tumor-to-muscle ratio. Biodistribution results confirmed that radioactivity uptake in the tumor was significantly higher than that in the muscle by more than five-fold (P<0.001). Furthermore, the relatively low bone uptake of [Al18F]NODA-MPAA-HTA suggested that defluorination did not occur in vivo. These preliminary results provide experimental evidence for further study of Al18F-labeled somatostatin analogues as tumor probes for PET imaging of NETs. Fluorine-18 is widely used as a radionuclide for the production of radiopharmaceuticals for positron emission tomography (PET). Due to its short half-life (T1/2,109.8min), its ease of production will facilitate the widespread dissemination of this radiopharmaceutical. A high-quality [Al18F]NODA-MPAA-HTA was synthesized with satisfactory yield. This radiopharmaceutical demonstrated higher tumor uptake and better tumor-to-muscle contrast, resulting to excellent image quality. These findings suggest that the novel 18F-labeled somatostatin analogue, [Al18F]NODA-MPAA-HTA, is a promising tool for PET imaging of NETs.

Positron Emission Tomography Molecular Imaging of the Major Neurodegenerative Disorders: Overview and Pictorial Essay, from a Nuclear Medicine Center's Perspective.

Computed tomography (CT) and magnetic resonance imaging (MRI) provide key structural information on brain pathophysiology. Positron emission tomography (PET) measures metabolism in the living brain; it plays an important role in molecular neuroimaging and is rapidly expanding its field of application to the study of neurodegenerative diseases. Different PET radiopharmaceuticals allow in vivo characterization and quantization of biological processes at the molecular and cellular levels, from which many neurodegenerative diseases develop. In addition, hybrid imaging tools such as PET/CT and PET/MRI support the utility of PET, enabling the anatomical mapping of functional data. In this overview, we describe the most commonly used PET tracers in the diagnostic work-up of patients with Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. We also briefly discuss the pathophysiological processes of tracer uptake in the brain, detailing their specific cellular pathways in clinical cases. This overview is limited to imaging agents already applied in human subjects, with particular emphasis on those tracers used in our department.

Expression of the excitatory opsin ChRERα can be traced longitudinally in rat and nonhuman primate brains with PET imaging.

Optogenetics is a widely used technology with potential for translational research. A critical component of such applications is the ability to track the location of the transduced opsin in vivo. To address this problem, we engineered an excitatory opsin, ChRERα (hChR2(134R)-V5-ERα-LBD), that could be visualized using positron emission tomography (PET) imaging in a noninvasive, longitudinal, and quantitative manner. ChRERα consists of the prototypical excitatory opsin channelrhodopsin-2 (ChR2) and the ligand-binding domain (LBD) of the human estrogen receptor α (ERα). ChRERα showed conserved ChR2 functionality and high affinity for [18F]16α-fluoroestradiol (FES), an FDA-approved PET radiopharmaceutical. Experiments in rats demonstrated that adeno-associated virus (AAV)-mediated expression of ChRERα enables neural circuit manipulation in vivo and that ChRERα expression could be monitored using FES-PET imaging. In vivo experiments in nonhuman primates (NHPs) confirmed that ChRERα expression could be monitored at the site of AAV injection in the primary motor cortex and in long-range neuronal terminals for up to 80 weeks. The anatomical connectivity map of the primary motor cortex identified by FES-PET imaging of ChRERα expression overlapped with a functional connectivity map identified using resting state fMRI in a separate cohort of NHPs. Overall, our results demonstrate that ChRERα expression can be mapped longitudinally in the mammalian brain using FES-PET imaging and can be used for neural circuit modulation in vivo.

In silico evaluation of new mangiferin-based Positron Emission Tomography radiopharmaceuticals through the inhibition of metalloproteinase-9

Metalloproteinase-9 (MMP-9) is a key protein in cancer advancement and metastasis owing to its ability to degrade some extracellular matrix components. Mangiferin, a natural polyphenolic compound, has demonstrated through experimental and theoretical studies to be a great anticancer agent for the selective inhibition of MMP-9. This work aimed to evaluate the utility of several fluorinated compounds obtained from MF as possible Positron Emission Tomography (PET) radiopharmaceuticals oriented to MMP-9. Density Functional Theory calculations of MF were made to obtain the most active sites toward electrophilic and nucleophilic reactions and propose a synthetic route to produce its fluorinated derivatives. The reactivity study allowed us to propose a late-stage synthetic route based on click chemistry to obtain three fluorinated MF-based derivatives. Molecular docking calculations suggested that the derivative F-propyl-MF could be suitable as PET radiopharmaceutical owing to the establishment of a five-coordinated complex with the catalytic Zn atom belonging to the active site of MMP-9, crucial factor in the inhibition of MMP-9.

Recent Advances in 64Cu/67Cu-Based Radiopharmaceuticals

Copper-64 (T1/2 = 12.7 h) is a positron and beta-emitting isotope, with decay characteristics suitable for both positron emission tomography (PET) imaging and radiotherapy of cancer. Copper-67 (T1/2 = 61.8 h) is a beta and gamma emitter, appropriate for radiotherapy β-energy and with a half-life suitable for single-photon emission computed tomography (SPECT) imaging. The chemical identities of 64Cu and 67Cu isotopes allow for convenient use of the same chelating molecules for sequential PET imaging and radiotherapy. A recent breakthrough in 67Cu production opened previously unavailable opportunities for a reliable source of 67Cu with high specific activity and purity. These new opportunities have reignited interest in the use of copper-containing radiopharmaceuticals for the therapy, diagnosis, and theranostics of various diseases. Herein, we summarize recent (2018–2023) advances in the use of copper-based radiopharmaceuticals for PET, SPECT imaging, radiotherapy, and radioimmunotherapy.

Spirocyclic Iodonium Ylides for Fluorine-18 Radiolabeling of Non-Activated Arenes: From Concept to Clinical Research.

Positron emission tomography (PET) is a powerful imaging tool for drug discovery, clinical diagnosis, and monitoring of disease progression. Fluorine-18 is the most common radionuclide used for PET, but advances in radiotracer development have been limited by the historical lack of methodologies and precursors amenable to radiolabeling with fluorine-18. Radiolabeling of electron-rich (hetero)aromatic rings remains a long-standing challenge in the production of PET radiopharmaceuticals. In this personal account, we discuss the history of spirocyclic iodonium ylide precursors, from inception to applications in clinical research, for the incorporation of fluorine-18 into complex non-activated (hetero)aromatic rings.

Update on PET Radiopharmaceuticals for Imaging Hepatocellular Carcinoma

Numerous positron emission tomography (PET) targets for detection and staging of hepatocellular cancer have been developed in recent years. Hepatocellular carcinomas (HCCs) are clinically and pathologically heterogeneous tumours with a high tendency to be aggressive and unresponsive to chemotherapy. Early detection is essential, and the need for an adequate imaging biomarker, which can overcome some of the limitations of conventional radiological imaging, is persistent. Flourine-18 (18F) flourodeoxyglucose (FDG), the most widely used PET radiopharmaceutical, has proven disappointing as a possible staple in the evaluation of HCC. This disappointment had led to experimentation with carious radiotracers, such as the choline derivatives, acetate, and prostate-specific membrane antigen, which appear to complement and/or enhance the role of FDG. In this study, we look at the various PET radiopharmaceuticals that have been used for imaging HCC and the particular pathways that they target in HCC and liver cancers.

In silico evaluation of new mangiferin-based Positron Emission Tomography radiopharmaceuticals through the inhibition of metalloproteinase-9. (Supporting files)

In silico evaluation of new mangiferin-based Positron Emission Tomography radiopharmaceuticals through the inhibition of metalloproteinase-9. (Supporting files)

Radiochemical, Computational, and Spectroscopic Evaluation of High-Denticity Desferrioxamine Derivatives DFO2 and DFO2p toward an Ideal Zirconium-89 Chelate Platform.

Desferrioxamine (DFO) has long been considered the gold standard chelator for incorporating [89Zr]Zr4+ in radiopharmaceuticals for positron emission tomography (PET) imaging. To improve the stability of DFO with zirconium-89 and to expand its coordination sphere to enable binding of large therapeutic radiometals, we have synthesized the highest denticity DFO derivatives to date: dodecadentate DFO2 and DFO2p. In this study, we describe the synthesis and characterization of a novel DFO-based chelator, DFO2p, which is comprised of two DFO strands connected by an p-NO2-phenyl linker and therefore contains double the chelating moieties of DFO (potential coordination number up to 12 vs 6). The chelator DFO2p offers an optimized synthesis comprised of only a single reaction step and improves water solubility relative to DFO2, but the shorter linker reduces molecular flexibility. Both DFO2 and DFO2p, each with 6 potential hydroxamate ligands, are able to reach a more energetically favorable 8-coordinate environment for Zr(IV) than DFO. The zirconium(IV) coordination environment of these complexes were evaluated by a combination of density functional theory (DFT) calculations and synchrotron spectroscopy (extended X-ray absorption fine structure), which suggest the inner-coordination sphere of zirconium(IV) to be comprised of the outermost four hydroxamate ligands. These results also confirm a single Zr(IV) in each chelator, and the hydroxide ligands which complete the coordination sphere of Zr(IV)-DFO are absent from Zr(IV)-DFO2 and Zr(IV)-DFO2p. Radiochemical stability studies with zirconium-89 revealed the order of real-world stability to be DFO2 > DFO2p ≫ DFO. The zirconium-89 complexes of these new high-denticity chelators were found to be far more stable than DFO, and the decreased molecular flexibility of DFO2p, relative to DFO2, could explain its decreased stability, relative to DFO2.

MODIFICATION OF [18F]FDG BY THE FORMATION OF A HYDRAZONE BOND

Purpose: The [18F]-fluorodeoxyglucose ([18F]-FDG) is known to be one of the most used radio-pharmaceuticals for positron emission tomography. [18F]-FDG allows the assessment of glycolytic activity, which is more enhanced in tumor cells than in normal cells. It is also used in the assessment of heart and neurological diseases. The aim of our work is to follow the possibility of modifying [18F]-fluorodeoxyglucose and to develop an indirect radiofluorination procedure applicable under standard clinical conditions. Material/Methods: In the clinic of nuclear medicine at the University Hospital Sta. Marina-Varna, for routine clinical purposes, [18F]-FDG is produced by the nucleophilic method of fluorination, using mannose triflate as a precursor. In addition to being used as a universal radiopharmaceutical, [18F]-FDG may be involved as a prosthetic group in biorthogonal reactions. [18F]-glycosylation by oxime or hydrazone formation is a chemoselective method for indirect radiofluorination of sensitive molecules. The process can improve the pharmacokinetics and stability of the labeled compounds in the blood. Results: We developed a method for modifying fluorine-deoxyglucose by forming a hydrazone bond with bifunctional tetrazine {3-[4-(6-phenyl-[1,2,4,5]-tetrazine-3-yl)-phenoxy]-propyl}-hydrazine) (Tz). The progress of the process and the product obtained were monitored by radio TLC. The radiolabeled tetrazine product will be used for future biorthogonal click reactions with trans-cyclooctene under physiological conditions.

Cyclotron production of 68Ga and "in house" preparation of positron emission tomography (PET) radiopharmaceuticals

Cyclotron production of 68Ga and "in house" preparation of positron emission tomography (PET) radiopharmaceuticals

Clinical practice in prostate PET imaging.

Positron emission tomography (PET) imaging in prostate cancer has advanced significantly in the past decade with prostate cancer targeted radiopharmaceuticals now playing a growing role in diagnosis, staging, and treatment. This narrative review focuses on the most commonly used PET radiopharmaceuticals in the USA: prostate-specific membrane antigen (PSMA), fluciclovine, and choline. 18F-fluorodeoxyglucose (FDG) is used in many other malignancies, but rarely in prostate cancer. Previous literature is discussed regarding each radiopharmaceutical's utility in the settings of screening/diagnosis, initial staging, biochemical recurrence, advanced disease, and evaluation prior to targeted radiopharmaceutical therapy and radiation therapy. PET imaging has demonstrated utility over traditional imaging in various scenarios; however, there are few head-to-head studies comparing PET radiopharmaceuticals. PSMA radiopharmaceuticals are the newest tracers developed and have unique properties and uses, especially at low prostate-specific antigen (PSA) levels. However, each PET radiopharmaceutical has different properties which can affect image interpretation. Choline and fluciclovine have minimal urinary activity, whereas PSMA agents can have high urinary activity which may affect locoregional disease evaluation. Of the three radiopharmaceuticals, only PSMA is approved for both diagnostic and therapeutic indications with 177Lu-PSMA. A variety of diagnostic PET radiotracers for prostate cancer allows for increased flexibility, especially in the setting of supply chain and medication shortages. For the time being, keeping a diverse group of PET radiopharmaceuticals for prostate cancer is justifiable.

Main challenges in radiation protection with emerging radionuclide therapies.

The recent development of radionuclide therapy and radioligand therapy has raised a call for achieving the highest quality standards, for either radiopharmacy or radiation protection. Novel radionuclides are now being used, either under the form of in-house production radiopharmaceuticals or available from companies. Over the last 20 years, they include radiolabeled microspheres for selective internal radiotherapy (SIRT), the introduction of the first commercially available alpha emitter radiopharmaceutical, 223Ra, and the radiosynoviorthesis which is highly variable across Europe. More important is the development of radioligand therapy, often called theranostics. In this concept, a diagnostic radiopharmaceutical can determine the chance of success of a therapeutic one. Typically, diagnostic radiopharmaceuticals for positron emission tomography, are labeled with 18F or 68Ga, such as the PSMA ligands or somatostatin analogs, and the therapeutic radiopharmaceutical is labeled with 177Lu. This has revolutionized the world of Nuclear Medicine, but also all concepts that shall be applied to properly apply quality assurance and radiation protection in the field. This article will follow the example of 131I as the main used radionuclide for therapy during the last 80 years. Proposals can be general, and in parallel expert's articles will give specific guidance on issues with particular radionuclides, i.e., alpha emitters and 177Lu. This article will also give insight in the radiation protection issues related to the use of microspheres radiolabeled with either 90Y or 166Ho.

Radiolabelling of peptides with tetrazine ligation based on the inverse electron-demand Diels-Alder reaction: rapid, catalyst-free and mild conversion of 1,4-dihydropyridazines to pyridazines.

Click chemistry reactions, such as the tetrazine ligation, based on the inverse-electron demand Diels-Alder (IEDDA), are chemoselective cycloaddition reactions widely used for chemical modifications and synthesis of biomolecule-based radiopharmaceuticals for positron emission tomography (PET). The reactions have potential also for pretargeted PET imaging. When used as a bioconjugation method in production of biomolecule-based radiopharmaceuticals, IEDDA-based tetrazine ligation has one significant drawback, namely the formation of a mixture comprising reduced metastable dihydropyridazines (DHPs) and oxidized cycloadducts. Conversion of the reduced DHPs to stable pyridazines requires oxidation, which is typically achieved by using oxidants or by photo-irradiated air-oxidation, both methods requiring added reagents or reaction times of several hours, not compatible with short-lived radionuclides. Here we report a mild, rapid, and catalyst-free conversion of the DHPs to pyridazines. In this study, a model peptide Tyr3-octreotide (TOC) was modified with polyethylene glycol (PEG) linkers and with trans-cyclooctenes (TCOs) for rapid IEDDA-mediated radiolabeling. Fluorine-18-labelled alkylammoniomethyltrifluoroborate ([18F]AmBF3) tetrazines were conjugated to the TCO-TOC analogs at room temperature for rapid synthesis of PET imaging agent candidates. The formed DHPs were successfully converted to the oxidized form, after heating the radiolabelled bioconjugates in aqueous solution (≥95% water) at 60 °C for a minimum of 10 minutes in the presence of air, resulting in one-pot back-to-back IEDDA reaction and DHP conversion. The water content of the reaction mixture was to be found critical for the coversion. Our finding offers a straightforward method for conversion of the metastable DHPs from the IEDDA-based tetrazine ligation to stable, oxidized pyridazines. The method is especially suitable for applications requiring rapid conversion.

PET and SPECT Imaging of ALS: An Educational Review.

Amyotrophic lateral sclerosis (ALS) is a disease leading to progressive motor degeneration and ultimately death. It is a complex disease that can take a significantly long time to be diagnosed, as other similar pathological conditions must be ruled out for a definite diagnosis of ALS. Noninvasive imaging of ALS has shed light on disease pathology and altered biochemistry in the ALS brain. Other than magnetic resonance imaging (MRI), two types of functional imaging, positron emission tomography (PET) and single photon emission computed tomography (SPECT), have provided valuable data about what happens in the brain of ALS patients compared to healthy controls. PET imaging has revealed a specific pattern of brain metabolism through [18F]FDG, while other radiotracers have uncovered neuroinflammation, changes in neuronal density, and protein aggregation. SPECT imaging has shown a general decrease in regional cerebral blood flow (rCBF) in ALS patients. This educational review summarizes the current state of ALS imaging with various PET and SPECT radiopharmaceuticals to better understand the pathophysiology of ALS.

Automated sulfur-[18F]fluoride exchange radiolabelling of a prostate specific membrane antigen (PSMA) targeted ligand using the GE FASTlab™ cassette-based platform.

Sulfur-[18F]fluoride exchange radiochemistry is a rapid and convenient method for incorporating fluorine-18 into biologically active molecules. We report a fully automated radiolabelling procedure for the synthesis of a [18F]SO3F-bearing prostate specific membrane antigen (PSMA) targeted ligand ([18F]5) using the GE FASTLab™ cassette-based platform in a 25.0 ± 2.6% radiochemical yield (decay corrected). Uptake in vitro and in vivo correlated with PSMA expression, and the radioligand exhibited favourable biodistribution and pharmacokinetic profiles.