Preclinical evaluation and pilot clinical study of [Ga]Ga-NOTA-H006 for non-invasive PET imaging of 5T4 oncofetal antigen.

Purpose: Trophoblast glycoprotein, the so-called 5T4, is an oncofetal antigen expressed in many different cancers. However, no 5T4-specific radioligand is employed in the clinic for non-invasive diagnosis. Thus, the aim of the current study was to develop a PET radiotracer for imaging 5T4 expression in preclinical and clinical stages.

Radiosynthesis and preclinical evaluations of [F]AlF-RESCA-5F7 as a novel molecular probe for HER2 tumor imaging.

HER2 overexpression is associated with various tumor types and prompted the development of targeted therapies. Previously, -[At]SGMAB-5F7 was developed as a HER2-targeted alpha therapy agent, demonstrating promising therapeutic efficacy in the preclinical stage. Aiming for an F-labeled tracer for companion diagnostics in clinical translation, we employed the AlF-RESCA strategy in our current work and investigated whether [F]AlF-RESCA-5F7 could visualize HER2 expression .

(Radio)Fluoro-iodination of Alkenes Enabled by a Hydrogen Bonding Donor Solvent.

We have developed a widely applicable (radio)fluoro-iodination of alkenes using readily available and easily handled KF (F). The reactions exhibited high functional group tolerance and needed only an ambient atmosphere. Furthermore, the resulting product could be further functionalized with various nucleophiles.

Hetero-aryl bromide precursor fluorine-18 radiosynthesis and preclinical evaluation of a novel positron emission tomography (PET) tracer [F]GSK1482160.

The purinergic P2X7 receptor (P2X7R), an ATP gated ion channel, is an important therapeutic target for various inflammatory immune and neurodegenerative diseases. A novel P2X7R targeting radiotracer GSK1482160 was radiosynthesized by hetero-aryl bromides precursor 10 with [F]EtNF, 20-30 % radiochemical yield, > 68 GBq/μmol specific activity, >98 % radiochemical purity. Evaluation in healthy male Sprague-Dawley rats revealed that [F]GSK1482160 ([F]11) was stably retained 87.

Preparation of [F]Alkenyl Fluorides Using No-Carrier-Added [F]AgF via Silver-Mediated Direct Radiofluorination of Alkynes.

We have developed a versatile method for the radiosynthesis of [F]alkenyl fluorides using no-carrier-added [F]AgF via the silver-mediated direct radiofluorination of alkynes. A variety of electron-deficient internal alkynes were compatible with this strategy and gave the desired product in good regioselectivity and RCY. This method could also be applied to the late-stage radiofluorination and showed potential in nuclear medicine development.

Sinapine Thiocyanate Inhibits the Proliferation and Mobility of Pancreatic Cancer Cells by Up-Regulating GADD45A.

Sinapine thiocyanate (ST), an alkaloid isolated from the seeds of cruciferous species, has exhibited anti-inflammatory, anti-malignancy, and anti-angiogenic effects in previous studies. However, the effects and molecular mechanisms of action of ST in pancreatic cancer (PC) are still limited. PC cells were treated with different concentrations (0, 20, 40, and 80 μM) of ST.

Synthesis of ArCFX and [F]Ar-CF via Cleavage of the Trifluoromethylsulfonyl Group.

A versatile synthesis of ArCFX and [F]Ar-CF type compounds from readily available ArCFSOCF has been developed. Diverse nucleophiles, including weak nucleophiles such as halides (F, Cl, Br, and I), RSH, and ROH, could react with ArCFSOCF efficiently to give the corresponding difluoromethylene products. The control experiments and the Hammett plot indicated that the reaction might proceed through a difluorocarbocation intermediate generated from the steric hindrance-assisted cleavage of the trifluoromethylsulfonyl group.

Transition-State Expansion: A Quantitative Model for Counterion Effects in Ionic Reactions.

Ionic reactions are the most common reactions used in chemical synthesis. In relatively low dielectric constant solvents (e.g.

Hydrogen-Bond-Donor Solvents Enable Catalyst-Free (Radio)-Halogenation and Deuteration of Organoborons.

A hydrogen bond donor solvent assisted (radio)halogenation and deuteration of organoborons has been developed. The reactions exhibited high functional group tolerance and needed only an ambient atmosphere. Most importantly, compared to literature methods, our conditions are more consistent with the principals of green chemistry (e.

Syntheses and in vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates.

A series of seventeen hydroxyl-containing sphingosine 1-phosphate receptor 1 (S1PR1) ligands were designed and synthesized. Their in vitro binding potencies were determined using [32P]S1P competitive binding assays. Compounds 10a, 17a, 17b, and 24 exhibited high S1PR1 binding potencies with IC50 values ranging from 3.

Syntheses and in vitro evaluation of new S1PR1 compounds and initial evaluation of a lead F-18 radiotracer in rodents.

Thirteen new sphingosine-1-phosphate receptor 1 (S1PR1) ligands were designed and synthesized by replacing azetidine-3-carboxylic acid moiety of compound 4 with new polar groups. The in vitro binding potency of these new analogs toward S1PR1 was determined. Out of 13 new compounds, four compounds 9a, 10c, 12b, and 16b displayed high S1PR1 binding potency with IC values of 13.

Kinetic modeling of [ F]VAT, a novel radioligand for positron emission tomography imaging vesicular acetylcholine transporter in non-human primate brain.

Molecular imaging of vesicular acetylcholine transporter (VAChT) in the brain provides an important cholinergic biomarker for the pathophysiology and treatment of dementias including Alzheimer's disease. In this study, kinetics modeling methods were applied and compared for quantifying regional brain uptake of the VAChT-specific positron emission tomography radiotracer, ((-)-(1-(-8-(2-fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)(4-fluorophenyl)-methanone) ([ F]VAT) in macaques. Total volume distribution (V ) estimates were compared for one-tissue compartment model (1TCM), two-tissue compartment model (2TCM), Logan graphic analysis (LoganAIF) and multiple linear analysis (MA1) with arterial blood input function using data from three macaques.

Synthesis and in vitro characterization of a P2X7 radioligand [I]TZ6019 and its response to neuroinflammation in a mouse model of Alzheimer disease.

The purinergic receptor P2X ligand-gated ion channel 7 (P2X7 receptor) is a promising imaging target to detect neuroinflammation. Herein, we report development of a potent iodinated radiotracer for P2X7 receptor, [I]TZ6019. The radiosynthesis of [I]TZ6019 was accomplished by allylic-tin precursor iodination using [I]NaI with good radiochemical yield of 85% and high radiochemical purity of > 99%.

Upregulated Sphingosine 1-Phosphate Receptor 1 Expression in Human and Murine Atherosclerotic Plaques.

Purpose: Dysregulation of sphingosine 1-phosphate receptor 1 (S1PR1) signaling contributes to inflammation-related pathophysiological changes in cardiovascular diseases including atherosclerosis (AS). S1PR1-targeting compounds significantly reduce lesion size in murine models of AS. Therefore, characterization of S1PR1 expression in vitro and in vivo in atherosclerotic plaque could enable mechanistic studies and inform S1PR1 targeted therapies.

Predicting Counterion Effects Using a Gold Affinity Index and a Hydrogen Bonding Basicity Index.

We have developed a gold affinity index and hydrogen bonding basicity index for counterions and have used these indexes to forecast their reactivity in cationic gold catalysis.

PET Study of Sphingosine-1-Phosphate Receptor 1 Expression in Response to Vascular Inflammation in a Rat Model of Carotid Injury.

Sphingosine-1-phosphate receptor (S1PR) activation plays a key role in vascular inflammatory response. Here, we report in vivo validation of [C]TZ3321, a potent S1PR1 radioligand, for imaging vascular inflammation in a rat model of carotid injury. The right common carotid artery of male adult Sprague-Dawley rats was injured by balloon overinflation that denuded the endothelium and distended the vessel wall.

Pharmacologic characterizations of a P2X7 receptor-specific radioligand, [11C]GSK1482160 for neuroinflammatory response.

Objective: The P2X7 receptor (P2X7R) is a key regulatory element in the neuroinflammatory cascade that provides a promising target for imaging neuroinflammation. GSK1482160, a P2X7R modulator with nanomolar binding affinity and high selectivity, has been successfully radiolabeled and utilized for imaging P2X7 levels in a mouse model of lipopolysaccharide-induced systemic inflammation. In the current study, we further characterized its binding profile and determined whether [C]GSK1482160 can detect changes in P2X7R expression in a rodent model of multiple sclerosis.

Acidic Co-Catalysts in Cationic Gold Catalysis.

A systematic study on the effects of Lewis or Brønsted acid co-catalysts in gold-catalyzed reactions was undertaken using representative reactions (O-, N-, and C-nucleophilic additions to alkynes). Through these reactions, it was demonstrated that an acidic co-catalyst can increase the catalyst turnover significantly, enabling practical reaction rates at competitive catalyst loadings (<1 mol %). Further investigation is currently underway to improve the understanding of the subtle principles underlying these experimental observations.

Comparison of [C]TZ1964B and [F]MNI659 for PET imaging brain PDE10A in nonhuman primates.

Phosphodiesterase 10A (PDE10A) inhibitors show therapeutic effects for diseases with striatal pathology. PET radiotracers have been developed to quantify in vivo PDE10A levels and target engagement for therapeutic interventions. The aim of this study was to compare two potent and selective PDE10A radiotracers, [C]TZ1964B and [F]MNI659 in the nonhuman primate (NHP) brain.

Revisiting the Influence of Silver in Cationic Gold Catalysis: A Practical Guide.

An excess amount of silver salt to generate cationic gold from a gold catalyst precursor such as L-Au-Cl almost always has adverse effects on the reactivity of the cationic gold catalyst. A preformed L-Au(+)X(-) complex, generated by sonication followed by centrifugation, increases the reactivity in a gold catalyzed reaction. The adverse silver effect might be caused by the interaction of silver salts with gold intermediates.

Potassium tris(triflyl)methide (KCTf3): a broadly applicable promoter for cationic metal catalysis.

KCTf3, a commercially available, easily handled neutral salt, enhanced the reaction rates and the chemical yields of a wide spectrum of cationic metal catalyzed reactions, ranging from traditional Lewis acid catalysis to transition metal catalysis.

Role of Hydrogen-Bonding Acceptors in Organo-Enamine Catalysis.

A hydrogen bond acceptor plays an important role in the catalytic cycle of organo-enamine catalysis. It can effectively influence the rate of reaction through hydrogen bonding interaction with enammonium (N-protonated enamine intermediate). Our findings are supported by both kinetic experiments and quantum chemical calculations.

Synthesis of Pyrrolidines and Pyrroles via Tandem Amination/Cyanation/Alkylation and Amination/Oxidation Sequences.

Starting from a primary amine-tethered alkyne , a copper-catalyzed three-component tandem amination/cyanation/alkylation sequence gives α-CN pyrrolidine in good yield and regioselectivity. Also, a silver mediated tandem amination/oxidation of a secondary amine-tethered alkyne produces functionalized pyrrole in good yield. All reactions were conducted in one pot without any protection/deprotection steps.

Designer HF-based fluorination reagent: highly regioselective synthesis of fluoroalkenes and gem-difluoromethylene compounds from alkynes.

Hydrogen fluoride (HF) and selected nonbasic and weakly coordinating (toward cationic metal) hydrogen-bond acceptors (e.g., DMPU) can form stable complexes through hydrogen bonding.

Efficient generation and increased reactivity in cationic gold via Brønsted acid or Lewis acid assisted activation of an imidogold precatalyst.

Brønsted or Lewis acid assisted activation of an imidogold precatalyst (L-Au-Pht, Pht = phthalimide) offers a superior way to generate cationic gold compared with the commonly used silver-based system. It is also broadly applicable for most common gold-catalyzed reactions. For reactions that require milder conditions, milder acids can be used for optimized efficiency.