In Vivo Stability Improvement of Astatobenzene Derivatives by Introducing Neighboring Substituents.

At is a promising radiohalogen for targeted α therapy. However, some astatinated compounds undergo deastatination in vivo, leading to unintended astatine accumulation in nontarget tissues. Recently, a group reported that the in vivo stability of an astato group on an alkyl group could be improved by placing specific substituents around the astato group.

Editorial for the Specific Issue of Radioprobes and Other Bioconjugates for Cancer Theranostics.

Theranostics refers to the systematic integration of targeted diagnostics and therapeutics, which promotes precise and personalized cancer treatment [...

New liposome-radionuclide-chelate combination for tumor targeting and rapid healthy tissue clearance.

Radionuclide imaging and therapy are promising methods for controlling systemic cancers; however, their clinical application has been limited by excessive radionuclide accumulation in healthy tissues. To minimize radionuclide accumulation in non-cancerous tissues while ensuring sufficient build up in tumors, we aimed to develop a method that controlled the in vivo dynamics of radionuclides post-administration. To this end, we describe a novel strategy that combines liposomes, a potent carrier system for drug delivery, with unique radionuclide-ligand complexes based on In-ethylenedicysteine.

Reduction of the Renal Radioactivity of In-DOTA-Labeled Antibody Fragments with a Linkage Cleaved by the Renal Brush Border Membrane Enzymes.

The interposition of a cleavable linkage by enzymes on the renal brush border membrane constitutes a promising approach for reducing the renal radioactivity levels of radiolabeled low-molecular-weight antibody fragments and constructs (LMW Abs). Herein, we applied the molecular design to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-based reagents for radiotheranostic applications with trivalent radiometals. DOTA or a derivative thereof was conjugated to a Fab through an FGK linkage ([In]In-DO3ABu-Bn-FGK-Fab or [In]In-DOTA-Bn-FGK-Fab).

Stability Estimation of Gallium Complexes of DOTA Derivatives for Radiotheranostic Applications.

1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid (DO3A) has been used to prepare Ga-labeled probes for the diagnostic counterpart of radiotheranostic applications. While DO3A provides stable complexes with therapeutic radionuclides such as Y, Lu, and Ac, further improvement of the stability of the Ga-DO3A complex is required. Considering the high stability of an intact Ga-DOTA complex, the stability of Ga complexes of DOTA and DO3A derivatives, including benzyl-DOTA (Bn-DOTA), was evaluated to gain fundamental knowledge for developing the next-generation radiotheranostic probes using Ga as a diagnostic counterpart.

Delivery of aPD-L1 antibody to i.p. tumors via direct penetration by i.p. route: Beyond EPR effect.

Chemotherapy for peritoneal dissemination is poorly effective owing to limited drug transfer from the blood to the intraperitoneal (i.p.) compartment after intravenous (i.

Synthesis and evaluation of a multifunctional probe with a high affinity for prostate-specific membrane antigen (PSMA) and bone.

Prostate cancer frequently metastasizes to the bone. Because patients with bone metastases suffer from skeletal-related events, the diagnosis and treatment of bone metastases in the early stage are important. In this study, to improve the sensitivity of detecting bone metastases in patients with prostate cancer, we designed, synthesized, and evaluated a multifunctional radiotracer, [Ga]Ga-D-PSMA-617 ([Ga]3), with an undeca-aspartic acid as a bone-seeking moiety between [Ga]Ga-DOTA and a prostate-specific membrane antigen (PSMA) ligand based on the lysine-urea-glutamate motif.

Synthesis and evaluation of a para-carboxylated benzyl-DOTA for labeling peptides and polypeptides.

Introduction: Radiolabeled peptides and low-molecular-weight (LMW) polypeptides show high and persistent radioactivity levels in the kidney. To develop a DOTA-based bifunctional chelating agent that provides a radiometabolite with a rapid elimination rate from the kidney, a para-carboxyl Bn-DOTA (p-COOH-Bn-DOTA) was designed, synthesized, and evaluated.

Methods: A precursor compound, p-COOH-Bn-DOTA(Bu), was synthesized in 9 steps using N-Boc-p-iodo-L-phenylalanine as the starting material.

Ex vivo imaging and analysis of ROS generation correlated with microglial activation in rat model with acute neuroinflammation induced by intrastriatal injection of LPS.

Neuroinflammation and oxidative stress are hallmarks of neurodegenerative diseases. Microglia, the major important regulators of neuroinflammation, are activated in response to excessive generation of reactive oxygen species (ROS) from damaged cells and resulting in elevated and sustained damages. However, the relationship between microglia and ROS-regulatory system in the early stages of neuroinflammation prior to the appearance of neuronal damages have not been elucidated in detail.

Neopentyl Glycol as a Scaffold to Provide Radiohalogenated Theranostic Pairs of High Stability.

The high stability of 2,2-dihydroxymethyl-3-[F]fluoropropyl-2-nitroimidazole ([F]DiFA) prompted us to evaluate neopentyl as a scaffold to prepare a radiotheranostic system with radioiodine and astatine. Three DiFA analogues with one, two, or without a hydroxyl group were synthesized. While all I-labeled compounds remained stable against nucleophilic substitution, only a I-labeled neopentyl glycol was stable against cytochrome P450 (CYP)-mediated metabolism and showed high stability against deiodination.

Evaluation of intracellular processes in quinolinic acid-induced brain damage by imaging reactive oxygen species generation and mitochondrial complex I activity.

Purpose: Our study aimed to elucidate the intracellular processes associated with quinolinic acid (QA)-induced brain injury by acquiring semiquantitative fluorescent images of reactive oxygen species (ROS) generation and positron emission tomography (PET) images of mitochondrial complex I (MC-I) activity.

Methods: Ex vivo fluorescent imaging with dihydroethidium (DHE) and PET scans with F-BCPP-EF were conducted at 3 h and 24 h after QA injection into the rat striatum. Immunohistochemical studies were performed 24 h after QA injection into the rat brain using monoclonal antibodies against neuronal nuclei (NeuN) and CD11b.

Preclinical evaluation of new α-radionuclide therapy targeting LAT1: 2-[At]astato-α-methyl-L-phenylalanine in tumor-bearing model.

Introduction: Targeted α-radionuclide therapy has attracted attention as a promising therapy for refractory cancers. However, the application is limited to certain types of cancer. Since L-type amino acid transporter 1 (LAT1) is highly expressed in various human cancers, we prepared an LAT1-selective α-radionuclide-labeled amino acid analog, 2-[At]astato-α-methyl-L-phenylalanine (2-[At]AAMP), and evaluated its potential as a therapeutic agent.

Aryl isocyanide derivative for one-pot synthesis of purification-free Tc-labeled hexavalent targeting probe.

Introduction: Tc-labeled hexavalent probes can be readily synthesized by the coordination of six equivalent isocyanide ligands towards Tc, and alkyl isocyanide ligands have been extensively used for preparing such probes. However, high ligand concentration (>1 mM) is generally required due to their insufficient coordination ability to Tc.

Methods And Results: In this study, we revealed that aryl isocyanide ligands, which have greater π-accepting ability compared with alkyl ones, provided Tc-labeled hexavalent probes in high radiochemical yields (>95%) even at low ligand concentration (50 μM).

Manipulating Pharmacokinetics of Purification-Free Tc-Labeled Bivalent Probes for In Vivo Imaging of Saturable Targets.

The accumulation of Tc-labeled probes targeting saturable systems of the body is hindered by the presence of a large excess of unlabeled ligands needed to ensure high radiochemical yields in a short reaction time. To address the issue, we recently reported a novel concept of a metal-coordination-mediated synthesis of a bivalent Tc-labeled probe from a monovalent ligand using d-penicillamine (Pen) as a chelating molecule and c(RGDfK) as a model targeting device. The Pen-conjugated c(RGDfK) via a hexanoate linkage (Pen-Hx-c(RGDfK)) provided a bivalent [Tc]Tc-[(Pen-Hx-c(RGDfK)) that possessed much higher integrin αβ binding affinity than Pen-Hx-c(RGDfK) and visualized a murine tumor without purification.

Renal brush border strategy: A developing procedure to reduce renal radioactivity levels of radiolabeled polypeptides.

The high and persistent radioactivity levels in the kidney constitute a long-unsettled problem of radiolabeled peptides and low molecular weight (LMW) polypeptides, especially when they are labeled with metallic radionuclides. To address the issue, we proposed an approach to liberate a radiometabolite of urinary excretion from covalently conjugated antibody Fab fragments, used as a representative LMW polypeptide, by the action of enzymes present on the brush border membrane of renal tubules. In this review, The history of our approach, starting from radioiodine to metallic radionuclides such as Re, Tc, Ga, and In, will be briefly described.

F-Labeled dihydromethidine: positron emission tomography radiotracer for imaging of reactive oxygen species in intact brain.

Dihydromethidine (DHM) labeled with 18F at the para position of the peripheral benzene ring was designed as a positron emission tomography (PET) radiotracer for non-invasive imaging of reactive oxygen species (ROS). This compound readily crosses the blood-brain barrier and is oxidized by ROS, and the oxidation product is retained intracellularly. PET imaging of ROS-producing rat brain microinfused with sodium nitroprusside identified specific brain regions with high ROS concentrations.

Poor outcome with anti-programmed death-ligand 1 (PD-L1) antibody due to poor pharmacokinetic properties in PD-1/PD-L1 blockade-sensitive mouse models.

Background: Recently, antiprogrammed cell death protein 1 (aPD-1) and antiprogrammed death-ligand 1 (aPD-L1) monoclonal antibodies (mAbs) have been approved. Even though aPD-1 and aPD-L1 mAbs target the same PD-1/PD-L1 axis, it is still unclear whether both mAbs exert equivalent pharmacological activity in patients who are sensitive to PD-1/PD-L1 blockade therapy, as there is no direct comparison of their pharmacokinetics (PK) and antitumor effects. Therefore, we evaluated the differences between both mAbs in PK and therapeutic effects in PD-1/PD-L1 blockade-sensitive mouse models.

Zn Complex of Diaminedithiol Tetradentate Ligand as a Stable Precursor for Tc-Labeled Compounds.

The diaminedithiol (NS) tetradentate ligand constitutes a useful chelating molecule for preparing Tc-labeled compounds of high in vivo stability in high radiochemical yields. However, since the thiol groups in the NS ligand are easy to be oxidized to disulfide bonds, they need to be protected with an appropriate protecting group, which hinders the broad applications of the NS ligand for radiopharmaceuticals. In this study, a Zn chelate of NS was evaluated as a precursor for purification-free Tc-labeled NS under the mild and simple procedure.

C-terminal-modified LY2510924: a versatile scaffold for targeting C-X-C chemokine receptor type 4.

C-X-C chemokine receptor type 4 (CXCR4) constitutes a promising target for tumor diagnosis and therapy. Herein, we evaluate a new 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated CXCR4 antagonist derived from LY2510924, FRM001, and its metal complexes as CXCR4-targeting probes. FRM001 was synthesized by modifying the C-terminus of LY2510924 with maleimido-mono-amide-DOTA via a cysteine linker.

The synthesis of a Tc-labeled tetravalent targeting probe upon isonitrile coordination to Tc for enhanced target uptake in saturable systems.

The presence of excess unlabeled ligands in the injectate hinders the target uptake of Tc-labeled targeting vectors. To address the issue, we previously developed a chemical design which provides a Tc-labeled trivalent RGD probe upon CN-βAla-Gly-Gly-c(RGDfK) (L) coordination to [Tc][Tc(CO)] core at pH 6.0.

Novel F-Labeled α-Methyl-Phenylalanine Derivative with High Tumor Accumulation and Ideal Pharmacokinetics for Tumor-Specific Imaging.

Positron emission tomography (PET) imaging with F-labeled α-methyl-substituted amino acids exerts significant influence on differential diagnosis of malignant tumors and tumor-like lesions. Exclusive uptake via L-type amino acid transporter 1 (LAT1), a tumor-specific transporter, accounts for their excellent tumor specificity and low background accumulation. However, further refinement and optimization in their tumor accumulation and pharmacokinetics are sorely needed.

Preparation of Tc-Labeled Mannan-S-Cysteine and Effect of Molecular Size of Mannan on Its Biodistribution.

Macrophage mannose receptor (MMR/CD206) is a promising target for the detection and identification of sentinel lymph node (SLN). MMR-targeting probes have been developed using mannosylated dextran, however, impairment of efficient targeting of SLN was often caused because of retention of injection site in which macrophages and dendritic cells exist. In this study, we prepared new MMR-targeting probes from yeast mannan (85 kDa), and its bioditribution was investigated.

A Simple Ex Vivo Semiquantitative Fluorescent Imaging Utilizing Planar Laser Scanner: Detection of Reactive Oxygen Species Generation in Mouse Brain and Kidney.

Objective: Oxidative stress plays an important role in the onset of many neuronal and peripheral disorders. We examined the feasibility of obtaining semiquantitative fluorescent images of reactive oxygen species (ROS) generation in mouse brain and kidney utilizing a planar laser scanner and dihydroethidium (DHE).

Methods: To investigate ROS generation in brain, sodium nitroprusside was injected into the striatum.

Successful Inflammation Imaging of Non-Human Primate Hearts Using an Antibody Specific for Tenascin-C.

Inflammation after myocardial infarction (MI) may be a major factor influencing ventricular remodeling, leading to congestive heart failure and arrhythmia. Therefore, inflammation in the heart needs to be monitored. Tenascin-C (TNC) is an extracellular matrix molecule not normally expressed, but it is strongly upregulated when associated with active inflammation.