Trace Metal Impurities Effects on the Formation of [Cu]Cu-diacetyl-bis(-methylthiosemicarbazone) ([Cu]Cu-ATSM).

[Cu]Cu-diacetyl-bis(-methylthiosemicarbazone) ([Cu]Cu-ATSM) is a radioactive hypoxia-targeting therapeutic agent being investigated in clinical trials for malignant brain tumors. For the quality management of [Cu]Cu-ATSM, understanding trace metal impurities' effects on the chelate formation of Cu and ATSM is important. In this study, we conducted coordination chemistry studies on metal-ATSM complexes.

A At-labelled mGluR1 inhibitor induces cancer senescence to elicit long-lasting anti-tumor efficacy.

Metabotropic glutamate receptor 1 (mGluR1), a key mediator of glutamatergic signaling, is frequently overexpressed in tumor cells and is an attractive drug target for most cancers. Here, we present a targeted radiopharmaceutical therapy strategy that antagonistically recognizes mGluR1 and eradicates mGluR1 human tumors by harnessing a small-molecule alpha (α)-emitting radiopharmaceutical, At-AITM. A single dose of At-AITM (2.

Whole-body PET tracking of a d-dodecapeptide and its radiotheranostic potential for PD-L1 overexpressing tumors.

Peptides that are composed of dextrorotary (d)-amino acids have gained increasing attention as a potential therapeutic class. However, our understanding of the fate of d-peptides is limited. This highlights the need for whole-body, quantitative tracking of d-peptides to better understand how they interact with the living body.

Automated radiosynthesis of [ C]MTP38-a phosphodiesterase 7 imaging tracer-using [ C]hydrogen cyanide for clinical applications.

We have developed 8-amino-3-(2S,5R-dimethyl-1-piperidyl)-[1,2,4]triazolo[4,3-a]pyrazine-5-[ C]carbonitrile ([ C]MTP38) as a positron emission tomography (PET) tracer for the imaging of phosphodiesterase 7. For the fully automated production of [ C]MTP38 routinely and efficiently for clinical applications, we determined the radiosynthesis procedure of [ C]MTP38 using [ C]hydrogen cyanide ([ C]HCN) as a PET radiopharmaceutical. Radiosynthesis of [ C]MTP38 was performed using an automated C-labeling synthesizer developed in-house within 40 min after the end of irradiation.

Development of a Stable Peptide-Based PET Tracer for Detecting CD133-Expressing Cancer Cells.

CD133 has been recognized as a prominent biomarker for cancer stem cells (CSCs), which promote tumor relapse and metastasis. Here, we developed a clinically relevant, stable, and peptide-based positron emission tomography (PET) tracer, [Cu]CM-2, for mapping CD133 protein in several kinds of cancers. Through the incorporation of a 6-aminohexanoic acid (Ahx) into the N terminus of a CM peptide, we constructed a stable peptide tracer [Cu]CM-2, which exhibited specific binding to CD133-positive CSCs in multiple preclinical tumor models.

Harnessing the PD-L1 interface peptide for positron emission tomography imaging of the PD-1 immune checkpoint.

Interface peptides that mediate protein-protein interactions (PPI) are a class of important lead compounds for designing PPI inhibitors. However, their potential as precursors for radiotracers has never been exploited. Here we report that the interface peptides from programmed death-ligand 1 (PD-L1) can be used in positron emission tomography (PET) imaging of programmed cell death 1 (PD-1) with high accuracy and sensitivity.

At-Labeled Polymer Nanoparticles for Targeted Radionuclide Therapy of Glucose-Dependent Insulinotropic Polypeptide Receptor (GIPR)-Overexpressed Cancer.

Targeted radionuclide therapy (TRT) provides new and safe opportunities for cancer treatment and management with high precision and efficiency. Here we have designed a novel semiconducting polymer nanoparticle (SPN)-based radiopharmaceutical (At-MeATE-SPN-GIP) for TRT against glucose-dependent insulinotropic polypeptide receptor (GIPR)-positive cancers to further explore the applications of nanoengineered TRT. At-MeATE-SPN-GIP was engineered via nanoprecipitation, followed by its functionalization with a glucose-dependent insulinotropic polypeptide (GIP) to target GIPR and deliver At for α therapy.

Automated radiosynthesis of two F-labeled tracers containing 3-fluoro-2-hydroxypropyl moiety, [F]FMISO and [F]PM-PBB3, via [F]epifluorohydrin.

Background: [F]Fluoromisonidazole ([F]FMISO) and 1-[F]fluoro-3-((2-((1E,3E)-4-(6-(methylamino)pyridine-3-yl)buta-1,3-dien-1-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol ([F]PM-PBB3 or [F]APN-1607) are clinically used radiotracers for imaging hypoxia and tau pathology, respectively. Both radiotracers were produced by direct F-fluorination using the corresponding tosylate precursors 1 or 2 and [F]F, followed by the removal of protecting groups. In this study, we synthesized [F]FMISO and [F]PM-PBB3 by F-fluoroalkylation using [F]epifluorohydrin ([F]5) for clinical applications.

Radiosynthesis and evaluation of 4-(6-[F]Fluoro-4-(5-isopropoxy-1-indazol-3-yl)pyridin-2-yl)morpholine as a novel radiotracer candidate targeting leucine-rich repeat kinase 2.

Mutations that increase leucine-rich repeat kinase 2 (LRRK2) activity in the brain are associated with Parkinson's disease. Here, we synthesized a novel compound 4-(6-fluoro-4-(5-isopropoxy-1-indazol-3-yl)pyridin-2-yl)morpholine (FIPM) and labeled it with fluorine-18 (F), to develop a positron emission tomography (PET) tracer for visualization of LRRK2 in the brain. FIPM showed high binding affinity for LRRK2 (IC = 8.

Marriage of black phosphorus and Cu as effective photothermal agents for PET-guided combination cancer therapy.

The use of photothermal agents (PTAs) in cancer photothermal therapy (PTT) has shown promising results in clinical studies. The rapid degradation of PTAs may address safety concerns but usually limits the photothermal stability required for efficacious treatment. Conversely, PTAs with high photothermal stability usually degrade slowly.

PET Imaging of VEGFR with a Novel Cu-Labeled Peptide.

Vascular endothelial growth factor receptors (VEGFRs) are well recognized as significant biomarkers of tumor angiogenesis. Herein, we have developed a first-of-its-kind peptide-based VEGFR positron emission tomography (PET) tracer. The novel [Cu]VEGF peptide possessed satisfactory radio-characteristics and showed good specificity for the visualization of VEGFR in various mouse models, in which the tumor-specific radioactivity uptake was highly correlated to the VEGFR expression level.

Radiosynthesis of [thiocarbonyl-C]disulfiram and its first PET study in mice.

[Thiocarbonyl-C]disulfiram ([C]DSF) was synthesized via iodine oxidation of [C]diethylcarbamodithioic acid ([C]DETC), which was prepared from [C]carbon disulfide and diethylamine. The decay-corrected isolated radiochemical yield (RCY) of [C]DSF was greatly affected by the addition of unlabeled carbon disulfide. In the presence of carbon disulfide, the RCY was increased up to 22% with low molar activity (A, 0.

I-IITM and At-AITM: Two Novel Small-Molecule Radiopharmaceuticals Targeting Oncoprotein Metabotropic Glutamate Receptor 1.

Targeted radionuclide therapy (TRT) targeting oncoproteins facilitates the delivery of therapeutic radionuclides to tumor tissues with high precision. Herein, we developed 2 new radiopharmaceuticals, 4-I-iodo- and 4-At-astato--[4-(6-(isopropylamino)pyridine-4-yl)-1,3-thiazol-2-yl]--methylbenzamide (I-IITM and At-AITM), targeting the ectopic metabotropic glutamate receptor 1 (mGluR1) in melanomas for TRT studies. I-IITM and At-AITM were synthesized by reacting a stannyl precursor with I-NaI and At in the presence of an oxidizing agent.

Correction: Developing native peptide-based radiotracers for PD-L1 PET imaging and improving imaging contrast by pegylation.

Correction for 'Developing native peptide-based radiotracers for PD-L1 PET imaging and improving imaging contrast by pegylation' by Kuan Hu et al., Chem. Commun.

Developing native peptide-based radiotracers for PD-L1 PET imaging and improving imaging contrast by pegylation.

Herein, a PD-L1 targeted native peptide was developed for PET imaging. 18F and 64Cu were utilized to label the peptide. To improve the pharmacokinetics and biodistribution of the tracers, the peptide was further pegylated to form star-like tetramers.

Development of a remote purification apparatus with disposable evaporator for the routine production of high-quality Cu for clinical use.

We developed a new apparatus for the routine production of Cu in clinical use. The apparatus has many disposable parts that stabilize the product quality (such that there is a low deviation of the concentrations of impurity metals in the product) and reduce the work load of preparation for routine production. We also developed a new evaporator using near-infrared heaters for disposable use.

[F]DAA1106: Automated radiosynthesis using spirocyclic iodonium ylide and preclinical evaluation for positron emission tomography imaging of translocator protein (18 kDa).

DAA1106 (N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide), is a potent and selective ligand for the translocator protein (18 kDa, TSPO) in brain mitochondrial fractions of rats and monkey (K = 0.043 and 0.188 nM, respectively).

Automated Synthesis of (rac)-, (R)-, and (S)-[ F]Epifluorohydrin and Their Application for Developing PET Radiotracers Containing a 3-[ F]Fluoro-2-hydroxypropyl Moiety.

To introduce the 3-[ F]fluoro-2-hydroxypropyl moiety into positron emission tomography (PET) radiotracers, we performed automated synthesis of (rac)-, (R)-, and (S)-[ F]epifluorohydrin ([ F]1) by nucleophilic displacement of (rac)-, (R)-, or (S)-glycidyl tosylate with F and purification by distillation. The ring-opening reaction of (R)- or (S)-[ F]1 with phenol precursors gave enantioenriched [ F]fluoroalkylated products without racemisation. We then synthesised (rac)-, (R)-, and (S)- 2-{5-[4-(3-[ F]fluoro-2-hydroxypropoxy)phenyl]-2-oxobenzo[d]oxazol-3(2H)-yl}-N-methyl-N-phenylacetamide ([ F]6) as novel radiotracers for the PET imaging of translocator protein (18 kDa) and showed that (R)- and (S)-[ F]6 had different radioactivity uptake in mouse bone and liver.

Small-scale production of Cu for a preclinical study via the Ni(α, p)Cu channel.

Introduction: Copper-67 is an attractive beta emitter for targeted radionuclide therapy. However, the availability of Cu limits its potential use in a wide range of applications. In this study, we propose an easy small-scale production of Cu using Ni target for a preclinical study.

Synthesis and evaluation of [Cu]PSMA-617 targeted for prostate-specific membrane antigen in prostate cancer.

We radiolabeled a ligand, PSMA-617, of prostate-specific membrane antigen (PSMA) with copper-64 (Cu), to evaluate the metabolism, biodistribution, and potential of [Cu]PSMA-617 for PET imaging of prostate cancer. [Cu]PSMA-617 was synthesized by heating PSMA-617 with [Cu]CuCl in buffer solution at 90°C for 5 min. uptake was determined in two cell lines of prostate cancer.

High-Contrast PET Imaging of Vasopressin V Receptors with a Novel Radioligand, C-TASP699.

Vasopressin 1B receptors (VRs) are abundantly expressed in the pituitary, and in vivo PET of VRs was recently enabled by our development of a specific radioligand, C-TASP0434299, derivatized from pyridopyrimidin-4-one. Here, we identified a novel pyridopyrimidin-4-one analog, --butyl-2-[2-(6-C-methoxypyridine-2-yl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-]pyrimidin-3(4)-yl]acetamide (C-TASP0410699, hereafter referred to as C-TASP699), as a potent VR radioligand producing a higher image contrast for the target than C-TASP0434299. In vitro properties of TASP699 were assessed by assaying its affinity for human VR and its selectivity for off-target molecules.

Efficient preparation of high-quality Cu for routine use.

Introduction: Copper-64 is an attractive radionuclide for positron emission tomography and is emerging as a radiotherapeutic agent. The demand of Cu with low metallic impurities has increased because of its wide applications when incorporated with antibodies, peptides, and proteins. In this study, we propose a new separation method to produce high-quality Cu using a cation exchange column, as well as an automated separation system suitable for large-scale production.

Radiosynthesis and quality control of [C]TASP457 as a clinically useful PET ligand for imaging of histamine H receptors in human brain.

Introduction: Recently, 6-[(1-cyclobutylpiperidin-4-yl)oxy]-1-(6-[C]methoxypyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one ([C]TASP457, [C]2) has been developed as a novel PET ligand for histamine H receptors in brain. [C]2 is potentially suitable for imaging H receptors in rat and monkey brains, which has motivated us to perform first-in-human study of [C]2 for qualifying H receptors in human brain. In this paper, we report an efficient radiosynthesis of [C]2 to obtain sufficient radioactivity and high quality for clinical application.

Development of TASP0410457 (TASP457), a novel dihydroquinolinone derivative as a PET radioligand for central histamine H3 receptors.

Background: Histamine H3 receptor (H3R) is a potential therapeutic target of sleep- and cognition-related disorders. The purpose of the present study is to develop a novel positron emission tomography (PET) ligand for H3Rs from dihydroquinolinone derivatives, which we previously found to have high affinity with these receptors.

Methods: Six compounds were selected from a dihydroquinolinone compound library based on structural capability for (11)C labeling and binding affinity for H3Rs.

Carbon-11 radiolabeling of an oligopeptide containing tryptophan hydrochloride via a Pictet-Spengler reaction using carbon-11 formaldehyde.

A procedure for the synthesis of a(11)C-labeled oligopeptide containing [1-(11)C]1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid ([1-(11)C]Tpi) from the corresponding Trp•HCl-containing peptides has been developed involving a Pictet-Spengler reaction with [(11) C]formaldehyde. The synthesis of [1-(11)C]Tpi from Trp and [(11)C]formaldehyde was examined as a model reaction with the aim of developing a facile and effective method for the labeling of peptides with carbon-11. The Pictet-Spengler reaction of Trp and [(11)C]formaldehyde in acidic media (TsOH or HCl) afforded the desired [1-(11)C]Tpi in a moderate radiochemical yield.