Fully automated radiosynthesis of [F]FCPPC for imaging microglia with PET.

Colony-stimulating factor 1 receptor (CSF1R) is almost exclusively expressed on microglia in the human brain and thus, has promise as a biomarker for imaging microglia density as a proxy for neuroinflammation. [C]CPPC is a radiotracer with selective affinity to CSF1R, and has been evaluated for in-human microglia PET imaging. The flourine-18 labeled CPPC derivative, 5-cyano-N-(4-(4-(2-[F]fluoroethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([F]FCPPC), was previously synthesized, however, with a low radiochemical yield using manual radiosynthesis.

Automated radiosynthesis of [C]CPPC for in-human PET imaging applications.

The macrophage colony-stimulating factor 1 receptor (CSF1R) is almost exclusively expressed in microglia, representing a biomarker target for imaging of microglia availability. [C]CPPC has specific binding affinity to CSF1R and suitable kinetic properties for PET imaging of microglia. However, previous studies reported a low radiochemical yield, motivating additional research to optimize [C]CPPC radiochemistry.

The First Human Application of an F-18-Labeled Tryptophan Analog for PET Imaging of Cancer.

Purpose: Preclinical studies showed the tryptophan analog PET radiotracer 1-(2-F-fluoroethyl)-L-tryptophan (F-FETrp) to accumulate in various tumors, including gliomas, and being metabolized via the immunosuppressive kynurenine pathway. In this first-in-human study, we tested the use F-FETrp-PET in patients with neuroendocrine and brain tumors.

Procedures: We applied dynamic brain imaging in patients with gliomas (n = 2) and multi-pass 3D whole-body PET scans in patients with neuroendocrine tumors (n =4).

Automated radiosynthesis of [F]FMPEP- for cannabinoid receptor PET imaging.

The cannabinoid subtype 1 receptor (CB1R) is highly expressed in the central nervous system and abnormalities in regional CB1R density are associated with neurodegenerative disorders. The PET tracer [F]FMPEP- is an inverse CB1R agonist which was shown to be suitable for non-invasive PET imaging. In this work, we reported the fully automated radiosynthesis of [F]FMPEP- on a Synthra RNplus research module.

Automated radiosynthesis of 1-(2-[ F]fluoroethyl)-L-tryptophan ([ F]FETrp) for positron emission tomography (PET) imaging of cancer in humans.

The radiotracer 1-(2-[ F]fluoroethyl)-L-tryptophan (L-[ F]FETrp or [ F]FETrp) is a substrate of indoleamine 2,3-dioxygenase, the initial and key enzyme of the kynurenine pathway associated with tumoral immune resistance. In preclinical positron emission tomography studies, [ F]FETrp is highly accumulated in a wide range of primary and metastatic cancers, such as lung cancer, prostate cancer, and gliomas. However, the clinical translation of this radiotracer into the first-in-human trial has not been reported, partially due to its racemization during radiofluorination which renders the purification of the final product challenging.

HPLC-free and cassette-based nucleophilic production of [F]FDOPA for clinical use.

Radiotracer 3,4-dihydroxy-6-[F]fluoro-L-phenylalanine (L-6-[F]fluorodopa or [F]FDOPA) is widely used for PET imaging of dopamine metabolism in several diseases including Parkinson's Disease, brain tumor, neuroendocrine tumors, and focal hyperinsulinism of infancy. In 2019, [F]FDOPA was approved by US FDA for detection of dopaminergic nerve terminals in the striatum of adult patients with suspected Parkinsonian Syndromes. A convenient and reliable method is desired for fully automated production of [F]FDOPA under cGMP compliance to meet the increasing clinical need.

Automated production of [F]Flortaucipir for PET imaging of tauopathies.

Radiotracer [F]Flortaucipir is an FDA-approved diagnostic agent for PET imaging of density and distribution of abnormal tau protein deposition (tauopathies) in Alzheimer's disease. A high-yield automated method for routine GMP-compliant [F]Flortaucipir production is desired to meet increasing clinical need. In this work, we reported an automated radiosynthesis of [F]Flortaucipir in a RNplus Research module and the quality control (QC) tests for human use under full GMP compliance.

Analysis of [C]Choline and [N]Ammonia using a single HPIC method.

A single HPIC method was developed and validated for the analysis of both [C]Choline and [N]Ammonia with the same setup. The HPIC system suitability tests were performed and [C]Choline and [N]Ammonia were used to verify their performance on this HPIC method. The HPIC setup and method provides qualitative and quantitative analysis information of [C]Choline and [N]Ammonia.

Cell Therapy by Ectopic Hepatocyte Transplantation Treats the Porcine Tyrosinemia Model of Acute Liver Failure.

The effectiveness of cell-based therapies to treat liver failure is often limited by the diseased liver environment. Here, we provide preclinical proof of concept for hepatocyte transplantation into lymph nodes as a cure for liver failure in a large-animal model with hereditary tyrosinemia type 1 (HT1), a metabolic liver disease caused by deficiency of fumarylacetoacetate hydrolase (FAH) enzyme. Autologous porcine hepatocytes were transduced with a lentiviral vector carrying the pig gene and transplanted into mesenteric lymph nodes.

Dual-Isotope SPECT Imaging with NIS Reporter Gene and Duramycin to Visualize Tumor Susceptibility to Oncolytic Virus Infection.

Noninvasive dual-imaging methods that provide an early readout on tumor permissiveness to virus infection and tumor cell death could be valuable in optimizing development of oncolytic virotherapies. Here, we have used the sodium iodide symporter (NIS) and I radiotracer to detect infection and replicative spread of an oncolytic vesicular stomatitis virus (VSV) in VSV-susceptible (MPC-11 tumor) versus VSV-resistant (CT26 tumor) tumors in BALB/c mice. In conjunction, tumor cell death was imaged simultaneously using technetium (Tc)-duramycin that binds phosphatidylethanolamine in apoptotic and necrotic cells.

Enhanced noninvasive imaging of oncology models using the NIS reporter gene and bioluminescence imaging.

Noninvasive bioluminescence imaging (BLI) of luciferase-expressing tumor cells has advanced pre-clinical evaluation of cancer therapies. Yet despite its successes, BLI is limited by poor spatial resolution and signal penetration, making it unusable for deep tissue or large animal imaging and preventing precise anatomical localization or signal quantification. To refine pre-clinical BLI methods and circumvent these limitations, we compared and ultimately combined BLI with tomographic, quantitative imaging of the sodium iodide symporter (NIS).

Cloning, function, and localization of human, canine, and Drosophila ZIP10 (SLC39A10), a Zn transporter.

Zinc (Zn) is the second most abundant trace element, but is considered a micronutrient, as it is a cofactor for many enzymes and transcription factors. Whereas Zn deficiency can cause cognitive immune or metabolic dysfunction and infertility, excess Zn is nephrotoxic. As for other ions and solutes, Zn is moved into and out of cells by specific membrane transporters: ZnT, Zip, and NRAMP/DMT proteins.

New transgenic NIS reporter rats for longitudinal tracking of fibrogenesis by high-resolution imaging.

Fibrogenesis is the underlying mechanism of wound healing and repair. Animal models that enable longitudinal monitoring of fibrogenesis are needed to improve traditional tissue analysis post-mortem. Here, we generated transgenic reporter rats expressing the sodium iodide symporter (NIS) driven by the rat collagen type-1 alpha-1 (Col1α1) promoter and demonstrated that fibrogenesis can be visualized over time using SPECT or PET imaging following activation of NIS expression by rotator cuff (RC) injury.

[F]Tetrafluoroborate ([F]TFB) and its analogs for PET imaging of the sodium/iodide symporter.

Sodium/iodide symporter (NIS)-mediated iodide uptake in thyroid follicular cells is the basis of clinical utilization of radioiodines. The cloning of the NIS gene enabled applications of NIS as a reporter gene in both preclinical and translational research. Non-invasive NIS imaging with radioactive iodides and iodide analogs has gained much interest in recent years for evaluation of thyroid cancer and NIS reporter expression.

Synthesis and evaluation of F-hexafluorophosphate as a novel PET probe for imaging of sodium/iodide symporter in a murine C6-glioma tumor model.

Noninvasive imaging of iodide uptake via the sodium/iodide symporter (NIS) has received great interest for evaluation of thyroid cancer and reporter imaging of NIS-expressing viral therapies. In this study, we investigate F-labeled hexafluorophosphate (HFP or PF) as a high-affinity iodide analog for NIS imaging. F-HFP was synthesized by radiofluorination of phosphorus pentafluoride·N-methylpyrrolidine complex and evaluated in human NIS (hNIS)-expressing C6 glioma cells and a C6 glioma xenograft mouse model.

Safety, pharmacokinetics, metabolism and radiation dosimetry of F-tetrafluoroborate (F-TFB) in healthy human subjects.

Background: F-Tetrafluoroborate (F-TFB) is a promising iodide analog for PET imaging of thyroid cancer and sodium/iodide symporter (NIS) reporter activity in viral therapy applications. The aim of this study was to evaluate the safety, pharmacokinetics, biodistribution, and radiation dosimetry of high-specific activity F-TFB in healthy human subjects.

Methods: F-TFB was synthesized with specific activity of 3.

First PET Imaging Studies With 63Zn-Zinc Citrate in Healthy Human Participants and Patients With Alzheimer Disease.

Abnormalities in zinc homeostasis are indicated in many human diseases, including Alzheimer disease (AD). Zn-zinc citrate was developed as a positron emission tomography (PET) imaging probe of zinc transport and used in a first-in-human study in 6 healthy elderly individuals and 6 patients with clinically confirmed AD. Dynamic PET imaging of the brain was performed for 30 minutes following intravenous administration of Zn-zinc citrate (∼330 MBq).

Curative ex vivo liver-directed gene therapy in a pig model of hereditary tyrosinemia type 1.

We tested the hypothesis that ex vivo hepatocyte gene therapy can correct the metabolic disorder in fumarylacetoacetate hydrolase-deficient (Fah(-/-)) pigs, a large animal model of hereditary tyrosinemia type 1 (HT1). Recipient Fah(-/-) pigs underwent partial liver resection and hepatocyte isolation by collagenase digestion. Hepatocytes were transduced with one or both of the lentiviral vectors expressing the therapeutic Fah and the reporter sodium-iodide symporter (Nis) genes under control of the thyroxine-binding globulin promoter.

Synthesis of 18F-Tetrafluoroborate via Radiofluorination of Boron Trifluoride and Evaluation in a Murine C6-Glioma Tumor Model.

Unlabelled: The sodium/iodide symporter (NIS) is under investigation as a reporter for noninvasive imaging of gene expression. Although (18)F-tetrafluoroborate ((18)F-TFB, (18)F-BF4 (-)) has shown promise as a PET imaging probe for NIS, the current synthesis method using isotopic exchange gives suboptimal radiochemical yield and specific activity. The aim of this study was to synthesize (18)F-TFB via direct radiofluorination on boron trifluoride (BF3) to enhance both labeling yield and specific activity and evaluation of specific activity influence on tumor uptake.

Production and Transport of Gaseous F-Synthons: F-Acyl Fluorides.

Fluorine-18 (F, T =109.7 min) is a positron-emitting isotope that has found extensive application as a radiolabel for positron emission tomography (PET). Although gaseous C-CO and C-CH are practically transported from cyclotron to radiochemistry processes, F-fluoride is routinely transported in aqueous solution because it is commonly produced by proton irradiation of O-enriched water.

Preparation and preliminary evaluation of 63Zn-zinc citrate as a novel PET imaging biomarker for zinc.

Unlabelled: Abnormalities of zinc homeostasis are indicated in many human diseases. A noninvasive imaging method for monitoring zinc in the body would be useful to understand zinc dynamics in health and disease. To provide a PET imaging agent for zinc, we have investigated production of (63)Zn (half-life, 38.

Cyclotron production of (68)Ga via the (68)Zn(p,n)(68)Ga reaction in aqueous solution.

The objective of the present work is to extend the applicability of the solution target approach to the production of (68)Ga using a low energy cyclotron. Since the developed method does not require solid target infrastructure, it offers a convenient alternative to (68)Ge/(68)Ga generators for the routine production of (68)Ga. A new solution target with enhanced heat exchange capacity was designed and utilized with dual foils of Al (0.

Multitarget-directed benzylideneindanone derivatives: anti-β-amyloid (Aβ) aggregation, antioxidant, metal chelation, and monoamine oxidase B (MAO-B) inhibition properties against Alzheimer's disease.

A novel series of benzylideneindanone derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer's disease. The in vitro studies showed that most of the molecules exhibited a significant ability to inhibit self-induced β-amyloid (Aβ(1-42)) aggregation (10.5-80.

Dual β2-adrenoceptor agonists-PDE4 inhibitors for the treatment of asthma and COPD.

We designed and synthesized a novel class of dual pharmacology bronchodilators targeting both β(2)-adrenoceptor and PDE4 by applying a multivalent approach. The most potent dual pharmacology molecule, compound 29, possessed good inhibitory activity on PDE4B2 (IC(50)=0.278 μM, which was more potent than phthalazinone, IC(50)=0.

Benzenediol-berberine hybrids: multifunctional agents for Alzheimer's disease.

We designed and synthesized a series of hybrid molecules, in an effort to identify novel multifunctional drug candidates for Alzheimer's disease (AD), by reacting berberine with benzenediol, melatonin, and ferulic acid. The products were evaluated for: (i) the ability to inhibit multiple cholinesterases (ChEs); (ii) the capacity to prevent amyloid β (Aβ) aggregation; and (iii) antioxidant activity. All of the derivatives were better antioxidants, and inhibited Aβ aggregation to a greater extent, than the lead compound, berberine.