Kinetic study of benzyl [1-14C]acetate as a potential probe for astrocytic energy metabolism in the rat brain: Comparison with benzyl [2-14C]acetate.

Brain uptake of [(14)C]acetate has been reported to be a useful marker of astrocytic energy metabolism. In addition to uptake values, the rate of radiolabeled acetate washout from the brain appears to reflect CO2 exhaustion and oxygen consumption in astrocytes. We measured the time-radioactivity curves of benzyl [1-(14)C]acetate ([1-(14)C]BA), a lipophilic probe of [1-(14)C]acetate, and compared it with that of benzyl [2-(14)C]acetate ([2-(14)C]BA) in rat brains.

Utility of Translocator Protein (18 kDa) as a Molecular Imaging Biomarker to Monitor the Progression of Liver Fibrosis.

Hepatic fibrosis is the wound healing response to chronic hepatic injury caused by various factors. In this study, we aimed to evaluate the utility of translocator protein (18 kDa) (TSPO) as a molecular imaging biomarker for monitoring the progression of hepatic fibrosis to cirrhosis. Model rats were induced by carbon tetrachloride (CCl4), and liver fibrosis was assessed.

Immuno-PET Imaging of HER3 in a Model in which HER3 Signaling Plays a Critical Role.

HER3 is overexpressed in various carcinomas including colorectal cancer (CRC), which is associated with poor prognosis, and is involved in the development of therapy resistance. Thus, an in vivo imaging technique is needed to evaluate the expression of HER3, an important therapeutic and diagnostic target. Here, we report successful HER3 PET imaging using a newly generated anti-human HER3 monoclonal antibody, Mab#58, and a mouse model of a HER3-overexpressing xenograft tumor.

Development of 1-N-(11)C-Methyl-L- and -D-Tryptophan for pharmacokinetic imaging of the immune checkpoint inhibitor 1-Methyl-Tryptophan.

1-Methyl-tryptophan (1MTrp) is known as a specific inhibitor targeting the immune-checkpoint protein indoleamine-2,3-dioxygenase, in two stereoisomers of levorotary (L) and dextrorotary (D). A long-standing debate exists in immunology and oncology: which stereoisomer has the potential of antitumor immunotherapy. Herein, we developed two novel radioprobes, 1-N-(11)C-methyl-L- and -D-tryptophan ((11)C-L-1MTrp and (11)C-D-1MTrp), without modifying the chemical structures of the two isomers, and investigated their utility for pharmacokinetic imaging of the whole body.

Synthesis and Preliminary PET Imaging Studies of a FAAH Radiotracer ([¹¹C]MPPO) Based on α-Ketoheterocyclic Scaffold.

Fatty acid amide hydrolase (FAAH) is one of the principle enzymes for metabolizing endogenous cannabinoid neurotransmitters such as anandamide, and thus regulates endocannabinoid (eCB) signaling. Selective pharmacological blockade of FAAH has emerged as a potential therapy to discern the endogenous functions of anandamide-mediated eCB pathways in anxiety, pain, and addiction. Quantification of FAAH in the living brain by positron emission tomography (PET) would help our understanding of the endocannabinoid system in these conditions.

Development of Novel PET Probes for Central 2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic Acid Receptors.

We document the development of PET probes for central AMPA receptors and their application to in vivo animal imaging. An initial screening of perampanel derivatives was performed to identify probe candidates. Despite the high autoradiographic contrast yielded by several radioligands, rat PET scans did not support their in vivo suitability.

Identification of a major radiometabolite of [11C]PBB3.

Introduction: [(11)C]PBB3 is a clinically used positron emission tomography (PET) probe for in vivo imaging of tau pathology in the brain. Our previous study showed that [(11)C]PBB3 was rapidly decomposed to a polar radiometabolite in the plasma of mice. For the pharmacokinetic evaluation of [(11)C]PBB3 it is important to elucidate the characteristics of radiometabolites.

In-vivo imaging of blood-brain barrier permeability using positron emission tomography with 2-amino-[3-11C]isobutyric acid.

Objective: The blood-brain barrier (BBB) limits the entry of some therapeutics into the brain, resulting in reduced efficacy. BBB-opening techniques have been developed to enhance the entry into the brain. However, a noninvasive, highly sensitive and quantitative method for evaluating the changes in BBB permeability induced by such techniques is needed to optimize treatment protocols.

Distinct binding of amyloid imaging ligands to unique amyloid-β deposited in the presubiculum of Alzheimer's disease.

Non-invasive determination of amyloid-β peptide (Aβ) deposition with radioligands serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). The polymorphic binding site on multimeric Aβ for current radioligands, however, is little understood. In this study, we investigated the binding of several radioligands including (11)C-Pittsburgh Compound B ((11)C-PiB), (3)H-AZD2184, and two recently developed compounds, (125)I-DRM106 and (125)I-DRK092, with unique presubicular Aβ deposits lacking interaction with the commonly used amyloid dyes FSB.

Prognostic value of (18) F-fluoroazomycin arabinoside PET/CT in patients with advanced non-small-cell lung cancer.

This study evaluated the prognostic value of positron emission tomography/computed tomography (PET/CT) using (18) F-fluoroazomycin arabinoside (FAZA) in patients with advanced non-small-cell lung cancer (NSCLC) compared with (18) F-fluorodeoxyglucose (FDG). Thirty-eight patients with advanced NSCLC (stage III, 23 patients; stage IV, 15 patients) underwent FAZA and FDG PET/CT before treatment. The PET parameters (tumor-to-muscle ratio [T/M] at 1 and 2 h for FAZA, maximum standardized uptake value for FDG) in the primary lesion and lymph node (LN) metastasis and clinical parameters were compared concerning their effects on progression-free survival (PFS) and overall survival (OS).

Development of the Fibronectin-Mimetic Peptide KSSPHSRN(SG)5RGDSP as a Novel Radioprobe for Molecular Imaging of the Cancer Biomarker α5β1 Integrin.

α5β1 Integrin, a fibronectin receptor, is becoming a pertinent therapeutic target and a promising prognostic biomarker for cancer patients. The aim of this study was to functionalize an α5β1-specific fibronectin-mimetic peptide sequence KSSPHSRN(SG)5RGDSP (called PR_b) as a positron emission tomography (PET) probe. PR_b was modified by addition of a β-alanine residue, conjugated with 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA), and radiolabeled with (18)F based on the chelation of (18)F-aluminum fluoride.

Preclinical evaluation of 2-amino-2-[11C]methyl-butanoic acid as a potential tumor-imaging agent in a mouse model.

Objective: C-labeled 2-amino-2-methyl-butanoic acid (Iva) was previously reported to provide high tumor uptake; however, the pharmacokinetic properties of C-labeled Iva have not been characterized. In the present study, we evaluated the potential of [C]Iva as a PET probe for tumor imaging.

Methods: [C]Iva was incubated in mouse serum for 60 min at 37°C and then analyzed by high-performance liquid chromatography and thin-layer chromatography.

PET Quantification of Tau Pathology in Human Brain with 11C-PBB3.

Unlabelled: Tau accumulation in the brain is a pathologic hallmark of Alzheimer disease and other tauopathies. Quantitative visualization of tau pathology in humans can be a powerful method as a diagnostic aid and for monitoring potential therapeutic interventions. We established methods of PET quantification of tau pathology with (11)C-PBB3 (2-((1E,3E)-4-(6-((11)C-methylamino)pyridin-3-yl)buta-1,3-dienyl) benzo[d]thiazol-6-ol), considering its radiometabolite entering the brain.

[18F]FEBMP: Positron Emission Tomography Imaging of TSPO in a Model of Neuroinflammation in Rats, and in vitro Autoradiograms of the Human Brain.

We evaluated the efficacy of 2-[5-(4-[(18)F]fluoroethoxy-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-methyl-N-phenylacetamide] ([(18)F]FEBMP) for positron emission tomography (PET) imaging of translocator protein (18 kDa, TSPO). Dissection was used to determine the distribution of [(18)F]FEBMP in mice, while small-animal PET and metabolite analysis were used for a rat model of focal cerebral ischemia. [(18)F]FEBMP showed high radioactivity uptake in mouse peripheral organs enriched with TSPO, and relatively high initial brain uptake (2.

A limited overlap between intratumoral distribution of 1-(5-fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole and copper-diacetyl-bis[N(4)-methylthiosemicarbazone].

Positron emission tomography (PET) imaging of tumor hypoxia provides valuable information for cancer treatment planning. Two types of PET tracers, nitroimidazole compounds and [62,64Cu] copper-diacetyl-bis[N(4)-methylthio- semicarbazone] (Cu-ATSM), have been used for imaging hypoxic tumors. High accumulation of these tracers in tumors was shown to predict poor prognosis.

A ¹¹C-labeled 1,4-dihydroquinoline derivative as a potential PET tracer for imaging of redox status in mouse brain.

A disturbance in redox balance has been implicated in the pathogenesis of a number of diseases. This study sought to examine the feasibility of imaging brain redox status using a (11)C-labeled dihydroquinoline derivative ([(11)C]DHQ1) for positron emission tomography (PET). The lipophilic PET tracer [(11)C]DHQ1 was rapidly oxidized to its hydrophilic form in mouse brain homogenate.

Improved Visualization and Specific Binding for Metabotropic Glutamate Receptor Subtype 1 (mGluR1) Using [11C]ITMM with Ultra-High Specific Activity in Small-Animal PET.

Metabotropic glutamate receptor subtype 1 (mGluR1) is a crucial target in the development of new medications to treat central nervous system (CNS) disorders. Recently, we developed N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-[11C]methoxy-N-methyl-benzamide ([11C]ITMM) as a useful positron emission tomography (PET) probe for mGluR1 in clinical studies. Here, we aimed to improve visualization and threshold of specific binding for mGluR1 using [11C]ITMM with ultra-high specific activity (SA) of > 3,500 GBq/μmol in rat brains.

Radiosynthesis and preliminary PET evaluation of glycogen synthase kinase 3β (GSK-3β) inhibitors containing [(11)C]methylsulfanyl, [(11)C]methylsulfinyl or [(11)C]methylsulfonyl groups.

Three compounds 1-3 containing methyl-sufanyl, sufinyl, or sulfonyl groups are strong inhibitors of glycogen synthase kinase 3β (GSK-3β), an enzyme associated with Alzheimer's disease. We labeled 1-3 with (11)C for a positron emission tomography (PET) brain imaging study. A novel thiophenol precursor 4 for radiosynthesis was prepared by reacting sulfoxide 2 with trifluoroacetic anhydride.

Preclinical assessment of early tumor response after irradiation by positron emission tomography with 2-amino-[3-¹¹C]isobutyric acid.

The positron emission tomography (PET) probe, 2-amino-[3-¹¹C]isobutyric acid ([3-¹¹C]AIB), is reported to accumulate less in inflammatory lesions than 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) and has the potential for evaluation of the efficacy of radiotherapy. To determine whether [3-¹¹C]AIB is useful to monitor early metabolic change in tumors after radiotherapy, we evaluated the temporal change in [3-¹¹C]AIB tumor uptake, tumor volume, histological features and expression of amino acid transporters early after radiotherapy in a mouse tumor model. PET with [3-¹¹C]AIB was conducted in mice bearing a subcutaneous tumor (SY, derived from small cell lung cancer) in two schedules: schedule 1, before (day -1) and after (days 1 and 3) 15 Gy of radiation and schedule 2, days -1, 1 and 5.

High-throughput screening with nanoimprinting 3D culture for efficient drug development by mimicking the tumor environment.

Anti-cancer drug development typically utilizes high-throughput screening with two-dimensional (2D) cell culture. However, 2D culture induces cellular characteristics different from tumors in vivo, resulting in inefficient drug development. Here, we report an innovative high-throughput screening system using nanoimprinting 3D culture to simulate in vivo conditions, thereby facilitating efficient drug development.

Inhibition of radical reactions for an improved potassium tert-butoxide-promoted (11) C-methylation strategy for the synthesis of α-(11) C-methyl amino acids.

α-(11) C-Methyl amino acids are useful tools for biological imaging studies. However, a robust procedure for the labeling of amino acids has not yet been established. In this study, the (11) C-methylation of Schiff-base-activated α-amino acid derivatives has been optimized for the radiosynthesis of various α-(11) C-methyl amino acids.

PET imaging of apoptosis in tumor-bearing mice and rabbits after paclitaxel treatment with (18)F(-)Labeled recombinant human His10-annexin V.

Monitoring response to chemo- or radiotherapy is of great importance in clinical practice. Apoptosis imaging serves as a very useful tool for the early evaluation of tumor response. The goal of this study was PET imaging of apoptosis with (18)F-labeled recombinant human annexin V linked with 10 histidine tag ((18)F-rh-His10-annexin V) in nude mice bearing an A549 tumor and rabbits bearing a VX2 lung cancer after paclitaxel therapy.

Quantification of central substance P receptor occupancy by aprepitant using small animal positron emission tomography.

Background: Central substance P receptors, termed NK-1 receptors, have been considered as therapeutic targets in the development of drugs against diverse conditions, including emesis, overactive bladder, and depression.

Methods: Here, we applied small animal positron emission tomography (PET) and a radioligand for NK-1 receptors ([(18)F]FE-SPA-RQ) for measuring occupancies of these receptors by a selective antagonist (aprepitant) in order to examine the validity of this in vivo imaging system for preclinical characterization of candidate agents acting on NK-1 receptors, and as a tool for predicting optimal doses in humans.

Results: PET in gerbils depicted high uptake in the striatum and dose-dependent displacement with increasing doses of aprepitant.

Synthesis and evaluation of 4-halogeno-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-[11C]methylbenzamide for imaging of metabotropic glutamate 1 receptor in melanoma.

Metabotropic glutamate 1 (mGlu1) receptor is found not only in the brain but also in melanomas and breast cancers. mGlu1 is a promising target for molecular imaging-based diagnosis and treatment of melanoma because its overexpression induces melanocyte carcinogenesis. Here we developed three PET tracers: 4-halogeno-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol- 2-yl]-N-[(11)C]methylbenzamide ([(11)C]4-6), which exhibited high uptake in target tumor and decreased uptake in nontarget brain tissues.

In vivo evaluation of a new ¹⁸F-labeled PET ligand, [¹⁸F]FEBU, for the imaging of I₂-imidazoline receptors.

Introduction: The functions of I₂-imidazoline receptors (I₂Rs) are unknown, but evidence exists for their involvement in various neuropsychiatric disorders. Although a few positron emission tomography (PET) I₂R ligands have been developed, of which [(11)C]FTIMD and [(11)C]BU99008 were evaluated as PET I₂R imaging ligands in monkeys, no human PET imaging study using an I₂R-selective PET ligand has been conducted yet. Thus, we synthesized an (18)F-labeled I₂R-selective ligand (BU99018 or FEBU, Ki for I₂Rs=2.