Spatial and temporal dynamics of HDACs class IIa following mild traumatic brain injury in adult rats.

The fundamental role of epigenetic regulatory mechanisms involved in neuroplasticity and adaptive responses to traumatic brain injury (TBI) is gaining increased recognition. TBI-induced neurodegeneration is associated with several changes in the expression-activity of various epigenetic regulatory enzymes, including histone deacetylases (HDACs). In this study, PET/CT with 6-([F]trifluoroacetamido)-1- hexanoicanilide ([F]TFAHA) to image spatial and temporal dynamics of HDACs class IIa expression-activity in brains of adult rats subjected to a weight drop model of diffuse, non-penetrating, mild traumatic brain injury (mTBI).

Noninvasive quantification of SIRT1 expression-activity and pharmacologic inhibition in a rat model of intracerebral glioma using 2-[F]BzAHA PET/CT/MRI.

Background: Several studies demonstrated that glioblastoma multiforme progression and recurrence is linked to epigenetic regulatory mechanisms. Sirtuin 1 (SIRT1) plays an important role in glioma progression, invasion, and treatment response and is a potential therapeutic target. The aim of this study is to test the feasibility of 2-[F]BzAHA for quantitative imaging of SIRT1 expression-activity and monitoring pharmacologic inhibition in a rat model of intracerebral glioma.

Molecular imaging HDACs class IIa expression-activity and pharmacologic inhibition in intracerebral glioma models in rats using PET/CT/(MRI) with [F]TFAHA.

HDAC class IIa enzymes (HDAC4, 5, 7, 9) are important for glioma progression, invasion, responses to TMZ and radiotherapy, and prognosis. In this study, we demonstrated the efficacy of PET/CT/(MRI) with [F]TFAHA for non-invasive and quantitative imaging of HDAC class IIa expression-activity in intracerebral 9L and U87-MG gliomas in rats. Increased accumulation of [F]TFAHA in 9L and U87-MG tumors was observed at 20 min post radiotracer administration with SUV of 1.

Molecular Imaging of Sirtuin1 Expression-Activity in Rat Brain Using Positron-Emission Tomography-Magnetic-Resonance Imaging with [F]-2-Fluorobenzoylaminohexanoicanilide.

Sirtuin 1 (SIRT1) is a class III histone deacetylase that plays significant roles in the regulation of lifespan, metabolism, memory, and circadian rhythms and in the mechanisms of many diseases. However, methods of monitoring the pharmacodynamics of SIRT1-targeted drugs are limited to blood sampling because of the invasive nature of biopsies. For the noninvasive monitoring of the spatial and temporal dynamics of SIRT1 expression-activity in vivo by PET-CT-MRI, we developed a novel substrate-type radiotracer, [F]-2-fluorobenzoylaminohexanoicanilide (2-[F]BzAHA).

Using Radiolabeled 3'-Deoxy-3'-F-Fluorothymidine with PET to Monitor the Effect of Dexamethasone on Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality in the United States, and pemetrexed-based therapies are regularly used to treat nonsquamous NSCLC. Despite widespread use, pemetrexed has a modest effect on progression-free survival, with varying efficacy between individuals. Recent work has indicated that dexamethasone, given to prevent pemetrexed toxicity, is able to protect a subset of NSCLC cells from pemetrexed cytotoxicity by temporarily suppressing the S phase of the cell cycle.

A Novel Substrate Radiotracer for Molecular Imaging of SIRT2 Expression and Activity with Positron Emission Tomography.

Purpose: The purpose of this study was to develop a SIRT2-specific substrate-type radiotracer for non-invasive PET imaging of epigenetic regulatory processes mediated by SIRT2 in normal and disease tissues.

Procedures: A library of compounds containing tert-butyloxycarbonyl-lysine-aminomethylcoumarin backbone was derivatized with fluoroalkyl chains 3-16 carbons in length. SIRT2 most efficiently cleaved the myristoyl, followed by 12-fluorododecanoic and 10-fluorodecanoic groups (K/K 716.

Assessment of Tryptophan Uptake and Kinetics Using 1-(2-18F-Fluoroethyl)-l-Tryptophan and α-11C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts.

Unlabelled: Abnormal tryptophan metabolism via the kynurenine pathway is involved in the pathophysiology of a variety of human diseases including cancers. α-C-methyl-l-tryptophan (C-AMT) PET imaging demonstrated increased tryptophan uptake and trapping in epileptic foci and brain tumors, but the short half-life of C limits its widespread clinical application. Recent in vitro studies suggested that the novel radiotracer 1-(2-F-fluoroethyl)-l-tryptophan (F-FETrp) may be useful to assess tryptophan metabolism via the kynurenine pathway.

Effects of capecitabine treatment on the uptake of thymidine analogs using exploratory PET imaging agents: F-FAU, F-FMAU, and F-FLT.

Background: A principal goal for the use of positron emission tomography (PET) in oncology is for real-time evaluation of tumor response to chemotherapy. Given that many contemporary anti-neoplastic agents function by impairing cellular proliferation, it is of interest to develop imaging modalities to monitor these pathways. Here we examined the effect of capecitabine on the uptake of thymidine analogs used with PET: 3'-deoxy-3'-[F]fluorothymidine (F-FLT), 1-(2'-deoxy-2'-[F]fluoro-β-D-arabinofuranosyl) thymidine (F-FMAU), and 1-(2'-deoxy-2'-[F]fluoro-β-D-arabinofuranosyl) uracil (F-FAU) in patients with advanced cancer.

Integrating Dynamic Positron Emission Tomography and Conventional Pharmacokinetic Studies to Delineate Plasma and Tumor Pharmacokinetics of FAU, a Prodrug Bioactivated by Thymidylate Synthase.

FAU, a pyrimidine nucleotide analogue, is a prodrug bioactivated by intracellular thymidylate synthase to form FMAU, which is incorporated into DNA, causing cell death. This study presents a model-based approach to integrating dynamic positron emission tomography (PET) and conventional plasma pharmacokinetic studies to characterize the plasma and tissue pharmacokinetics of FAU and FMAU. Twelve cancer patients were enrolled into a phase 1 study, where conventional plasma pharmacokinetic evaluation of therapeutic FAU (50-1600 mg/m ) and dynamic PET assessment of F-FAU were performed.

Novel Histone Deacetylase Class IIa Selective Substrate Radiotracers for PET Imaging of Epigenetic Regulation in the Brain.

Histone deacetylases (HDAC's) became increasingly important targets for therapy of various diseases, resulting in a pressing need to develop HDAC class- and isoform-selective inhibitors. Class IIa deacetylases possess only minimal deacetylase activity against acetylated histones, but have several other client proteins as substrates through which they participate in epigenetic regulation. Herein, we report the radiosyntheses of the second generation of HDAC class IIa-specific radiotracers: 6-(di-fluoroacetamido)-1-hexanoicanilide (DFAHA) and 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]-TFAHA).

Radiosynthesis of (11)C-Levetiracetam: A Potential Marker for PET Imaging of SV2A Expression.

The multistep preparation of (11)C-levetiracetam ((11)C-LEV) was carried out by a one-pot radiosynthesis with 8.3 ± 1.6% (n = 8) radiochemical yield in 50 ± 5.

15O PET measurement of blood flow and oxygen consumption in cold-activated human brown fat.

Unlabelled: Although it has been believed that brown adipose tissue (BAT) depots disappear shortly after the perinatal period in humans, PET imaging using the glucose analog (18)F-FDG has shown unequivocally the existence of functional BAT in adult humans, suggesting that many humans retain some functional BAT past infancy. The objective of this study was to determine to what extent BAT thermogenesis is activated in adults during cold stress and to establish the relationship between BAT oxidative metabolism and (18)F-FDG tracer uptake.

Methods: Twenty-five healthy adults (15 women and 10 men; mean age ± SD, 30 ± 7 y) underwent triple-oxygen scans (H2(15)O, C(15)O, and (15)O2) as well as measurements of daily energy expenditure (DEE; kcal/d) both at rest and after exposure to mild cold (15.

Assessment of oxidative metabolism in brown fat using PET imaging.

Objective: Although it has been believed that brown adipose tissue (BAT) depots disappear shortly after the perinatal period in humans, positron emission tomography (PET) imaging using the glucose analog ¹⁸F-deoxy-d-glucose (FDG) has shown unequivocally the existence of functional BAT in humans, suggesting that most humans have some functional BAT. The objective of this study was to determine, using dynamic oxygen-15 (¹⁵O) PET imaging, to what extent BAT thermogenesis is activated in adults during cold stress and to establish the relationship between BAT oxidative metabolism and FDG tracer uptake.

Methods: Fourteen adult normal subjects (9F/5M, 30 ± 7 years) underwent triple oxygen scans (H₂¹⁵O, C¹⁵O, ¹⁵O₂) as well as indirect calorimetric measurements at both rest and following exposure to mild cold (16°C).

Tryptophan metabolism in breast cancers: molecular imaging and immunohistochemistry studies.

Introduction: Tryptophan oxidation via the kynurenine pathway is an important mechanism of tumoral immunoresistance. Increased tryptophan metabolism via the serotonin pathway has been linked to malignant progression in breast cancer. In this study, we combined quantitative positron emission tomography (PET) with tumor immunohistochemistry to analyze tryptophan transport and metabolism in breast cancer.

Fully automated production of 11C-doxepin for PET imaging histamine H1 receptor.

Objectives: (11)C-Doxepin is an established positron emission tomography (PET) probe for imaging the histamine H1 receptor, which is associated with various neurological disorders and allergic diseases. A fully automated current Good Manufacturing Practices (cGMP)-compliant radiosynthesis is therefore desirable in order to facilitate clinical PET studies. We report here a fully automated production method for (11)C-doxepin using a multipurpose PET module for clinical use.

Herpes simplex virus thymidine kinase imaging in mice with (1-(2'-deoxy-2'-[18F]fluoro-1-β-D-arabinofuranosyl)-5-iodouracil) and metabolite (1-(2'-deoxy-2'-[18F]fluoro-1-β-D-arabinofuranosyl)-5-uracil).

Purpose: FIAU, (1-(2'-deoxy-2'-fluoro-1-β-D-arabinofuranosyl)-5-iodouracil) has been used as a substrate for herpes simplex virus thymidine kinases (HSV-TK and HSV-tk, for protein and gene expression, respectively) and other bacterial and viral thymidine kinases for noninvasive imaging applications. Previous studies have reported the formation of a de-iodinated metabolite of 18F-FIAU. This study reports the dynamic tumor uptake, biodistribution, and metabolite contribution to the activity of 18F-FIAU seen in HSV-tk gene expressing tumors and compares the distribution properties with its de-iodinated metabolite 18F-FAU.

Quantification of tryptophan transport and metabolism in lung tumors using PET.

Unlabelled: Abnormal tryptophan metabolism catalyzed by indoleamine 2,3-dioxygenase may play a prominent role in tumor immunoresistance in many tumor types, including lung tumors. The goal of this study was to evaluate the in vivo kinetics of alpha-(11)C-methyl-l-tryptophan (AMT), a PET tracer for tryptophan metabolism, in human lung tumors.

Methods: Tracer transport and metabolic rates were evaluated in 18 lesions of 10 patients using dynamic PET/CT with AMT.

Analysis and reproducibility of 3'-Deoxy-3'-[18F]fluorothymidine positron emission tomography imaging in patients with non-small cell lung cancer.

Purpose: Imaging tumor proliferation with 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) and positron emission tomography is being developed with the goal of monitoring antineoplastic therapy. This study assessed the methods to measure FLT retention in patients with non-small cell lung cancer (NSCLC) to measure the reproducibility of this approach.

Experimental Design: Nine patients with NSCLC who were untreated or had progressed after previous therapy were imaged twice using FLT and positron emission tomography within 2 to 7 days.

Tumor imaging using 1-(2'-deoxy-2'-18F-fluoro-beta-D-arabinofuranosyl)thymine and PET.

Unlabelled: The kinetics of 1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)thymine (FMAU) were studied using PET to determine the most appropriate and simplest approach to image acquisition and analysis. The concept of tumor retention ratio (TRR) is introduced and validated.

Methods: Ten patients with brain (n = 4) or prostate (n = 6) tumors were imaged using (18)F-FMAU PET (mean dose, 369 MBq).

Microglial activation in perinatal rabbit brain induced by intrauterine inflammation: detection with 11C-(R)-PK11195 and small-animal PET.

Unlabelled: Intrauterine infection can lead to a fetal inflammatory response syndrome that has been implicated as one of the causes of perinatal brain injury leading to periventricular leukomalacia (PVL) and cerebral palsy. The presence of activated microglial cells has been noted in autopsy specimens of patients with PVL and in models of neonatal hypoxia and ischemia. Activated microglial cells can cause oligodendrocyte damage and white matter injury by release of inflammatory cytokines and production of excitotoxic metabolites.

Biodistribution, PET, and radiation dosimetry estimates of HSV-tk gene expression imaging agent 1-(2'-Deoxy-2'-18F-Fluoro-beta-D-arabinofuranosyl)-5-iodouracil in normal dogs.

Unlabelled: FIAU is of interest as a potential reporter probe to monitor herpes simplex virus thymidine kinase (HSV-tk) gene expression and bacterial infections. This study investigates the biodistribution, metabolism, and DNA uptake of 1-(2'-deoxy-2'-(18)F-fluoro-beta-d-arabinofuranosyl)-5-iodouracil ((18)F-FIAU) in normal dogs.

Methods: Four normal dogs were intravenously administered (18)F-FIAU.

Quantification of protein synthesis in the human brain using L-[1-11C]-leucine PET: incorporation of factors for large neutral amino acids in plasma and for amino acids recycled from tissue.

Unlabelled: The rate of incorporation of exogenous amino acids into brain proteins is indicative of the protein synthesis rate (PSR). The objective of this study was to assess the effect of plasma concentrations of leucine and large neutral amino acids (LNAAs) on the unidirectional uptake rate constant (Kcplx) of l-[1-(11)C]-leucine in the brain and to estimate the amino acid pool recycled from tissue.

Methods: Twenty-seven healthy adult volunteers (11 men and 16 women; age range, 20-50 y) underwent dynamic l-[1-(11)C]-leucine PET with arterial blood sampling.

Biodistribution and radiation dosimetry estimates of 1-(2'-deoxy-2'-(18)F-Fluoro-1-beta-D-arabinofuranosyl)-5-bromouracil: PET imaging studies in dogs.

Unlabelled: This study reports on the biodistribution and radiation estimates of 1-(2'-deoxy-2'-(18)F-fluoro-1-beta-d-arabinofuranosyl)-5-bromouracil ((18)F-FBAU), a potential tracer for imaging DNA synthesis.

Methods: Three normal dogs were intravenously administered (18)F-FBAU and a dynamic PET scan was performed for 60 min over the upper abdomen followed by a whole-body scan for a total of 150 min. Blood samples were collected at stipulated time intervals to evaluate tracer clearance and metabolism.

Imaging the pharmacokinetics of [F-18]FAU in patients with tumors: PET studies.

Purpose: FAU (1-(2'-deoxy-2'-fluoro-beta-D: -arabinofuranosyl) uracil) can be phosphorylated by thymidine kinase, methylated by thymidylate synthase, followed by DNA incorporation and thus functions as a DNA synthesis inhibitor. This first-in-human study of [F-18]FAU was conducted in cancer patients to determine its suitability for imaging and also to understand its pharmacokinetics as a potential antineoplastic agent.

Methods: Six patients with colorectal (n = 3) or breast cancer (n = 3) were imaged with [F-18]FAU.

A simplified analysis of [18F]3'-deoxy-3'-fluorothymidine metabolism and retention.

Purpose: [18F]3'-deoxy-3'-fluorothymidine (FLT) is a thymidine analog developed for imaging tumor proliferation with positron emission tomography (PET). To quantitatively assess images, the blood activities of FLT and its glucuronidated metabolite were measured and its kinetics analyzed. This study sought to limit the number of blood samples needed to measure FLT retention.