Search

Simple Summary: This research study focuses on the P-cadherin protein, which is found in many types of tumors, and could be a potential target for therapy. FF-21101, a human–mouse chimeric monoclonal antibody that targets P-cadherin, was labeled with indium-111(111In) and investigated for biodistribution and radiation doses in six cynomolgus macaques. To assess the radiation profile distribution and clearance of FF-21101(111In), we performed whole-body imaging and generated time–activity curves. The lungs, spleen, liver, kidneys, and heart wall received the highest radiation dose estimates for FF-21101(111In). These findings led us to estimate the radiation doses that would be delivered to different organs if this antibody was labeled with yttrium-90 (90Y) and used in targeted radioimmunotherapy in patients. FF-21101 shows potential for clinical application in humans, according to biodistribution data obtained from macaques. Based on these results, an investigational new drug application was filed with the FDA for a Phase I clinical trial. P-cadherin is associated with a wide range of tumor types, making it an attractive therapeutic target. FF-21101 is a human–mouse chimeric monoclonal antibody (mAb) directed against human P-cadherin, which has been radioconjugated with indium-111 (111In) utilizing a DOTA chelator. We investigated the biodistribution of FF-21101(111In) in cynomolgus macaques and extrapolated the results to estimate internal radiation doses of 111In- and yttrium-90 (90Y)-FF-21101 for targeted radioimmunotherapy in humans. Whole-body planar and SPECT imaging were performed at 0, 2, 24, 48, 72, 96, and 120 h post-injection, using a dual-head gamma camera. Volumes of interest of identifiable source organs of radioactivity were defined on aligned reference CT and serial SPECT images. Organs with the highest estimated dose values (mSv/MBq) for FF-21101(111In) were the lungs (0.840), spleen (0.816), liver (0.751), kidneys (0.629), and heart wall (0.451); and for FF-21101(90Y) dose values were: lungs (10.49), spleen (8.21), kidneys (5.92), liver (5.46), and heart wall (2.61). FF-21101(111In) exhibits favorable biodistribution in cynomolgus macaques and estimated human dosimetric characteristics. Data obtained in this study were used to support the filing of an investigational new drug application with the FDA for a Phase I clinical trial. [ABSTRACT FROM AUTHOR]

Purpose: Metabolic reprogramming plays an important role in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). Currently, positron emission tomography (PET) reporters are not used clinically to visualize altered glutamine metabolism in ccRCC, which greatly hinders detection, staging, and real-time therapeutic assessment. We sought to determine if (2S,4R)-4-[18F]fluoroglutamine ([18F]FGln) could be used to interrogate altered glutamine metabolism in ccRCC lesions in the lung. Procedures: We generated a novel ccRCC lung lesion model using the ccRCC cell line UMRC3 stably transfected with GFP and luciferase constructs. This cell line was used for characterization of [18F]FGln uptake and retention by transport analysis in cell culture and by PET/MRI (magnetic resonance imaging) in animal models. Tumor growth in animal models was monitored using bioluminescence (BLI) and MRI. After necropsy, UMRC3 tumor growth in lung tissue was verified by fluorescence imaging and histology. Results: In UMRC3 cells, [18F]FGln cell uptake was twofold higher than cell uptake in normal kidney HEK293 cells. Tracer cell uptake was reduced by 60–90% in the presence of excess glutamine in the media and by 20–50% upon treatment with V-9302, an inhibitor of the major glutamine transporter alanine-serine-cysteine transporter 2 (ASCT2). Furthermore, in UMRC3 cells, [18F]FGln cell uptake was reduced by siRNA knockdown of ASCT2 to levels obtained by the addition of excess exogenous glutamine. Conversely, [18F]FGln cellular uptake was increased in the presence of the glutaminase inhibitor CB-839. Using simultaneous PET/MRI for visualization, retention of [18F]FGln in vivo in ccRCC lung tumors was 1.5-fold greater than normal lung tissue and twofold greater than muscle. In ccRCC lung tumors, [18F]FGln retention did not change significantly upon treatment with CB-839. Conclusions: We report one of the first direct orthotopic mouse models of ccRCC lung lesions. Using PET/MR imaging, lung tumors were easily discerned from normal tissue. Higher uptake of [18F]FGln was observed in a ccRCC cell line and lung lesions compared to HEK293 cells and normal lung tissue, respectively. [18F]FGln cell uptake was modulated by exogenous glutamine, V-9302, siRNA knockdown of ASCT2, and CB-839. Interestingly, in a pilot therapeutic study with CB-839, we observed no difference in treated tumors relative to untreated controls. This was in contrast with cellular studies, where CB-839 increased glutamine uptake. [ABSTRACT FROM AUTHOR]

The management of CNS tumors is limited by the blood-brain barrier (BBB), a vascular interface that restricts the passage of most molecules from the blood into the brain. Here we show that phage particles targeted with certain ligand motifs selected in vivo from a combinatorial peptide library can cross the BBB under normal and pathological conditions. Specifically, we demonstrated that phage clones displaying an ironmimic peptide were able to target a protein complex of transferrin and transferrin receptor (TfR) through a non-canonical allosteric binding mechanism and that this functional protein complex mediated transport of the corresponding viral particles into the normal mouse brain. We also showed that, in an orthotopic mouse model of human glioblastoma, a combination of TfR overexpression plus extended vascular permeability and ligand retention resulted in remarkable brain tumor targeting of chimeric adeno-associated virus/phage particles displaying the iron-mimic peptide and carrying a gene of interest. As a proof of concept, we delivered the HSV thymidine kinase gene for molecular-genetic imaging and targeted therapy of intracranial xenografted tumors. Finally, we established that these experimental findings might be clinically relevant by determining through human tissue microarrays that many primary astrocytic tumors strongly express TfR. Together, our combinatorial selection system and results may provide a translational avenue for the targeted detection and treatment of brain tumors., Introduction Historically, the blood-brain barrier (BBB) has been considered the major impediment to the systemic treatment of CNS diseases (1), (2). Access to the brain via its capillaries is obstructed [...]

Abstract: Introduction: 1′-[18 F]Fluoroethyl-β-d-lactose ([18 F]FEL) is a new PET imaging agent for early detection of pancreatic cancer and hepatocellular carcinoma. We previously reported the syntheses of [18 F]FEL using a bromo- and a tosyl- precursor, followed by an improved method using a nosyl-precursor. However, some steps in the synthesis of the precursor appeared to be problematic producing low yields. Here, we report on an optimized method for synthesis of the precursor and production of [18 F]FEL; we also describe [18 F]FEL’s formulation and stability. Methods: Acetylation of d-lactose 1 was performed following a literature procedure to obtain 1′,2′,3′,6′,2,3,4,6-d-lactose octa-acetate 2a/2b. Bromination of 2a/2b was performed using HBr/acetic acid to produce 1'-bromo-2′,3′,6′,2,3,4,6-hepta-O-acetyl-α-d-lactose 3. Coupling of 3 with ethylene glycol was performed in the presence of Ag-tosylate and an excess of ethylene glycol to produce 4a. Compound 4a was reacted with p-nitrophenylsulfonyl chloride to produce the nosyl derivative 5. Radiofluorination of 5 was performed using K[18 F]fluoride/kryptofix to obtain 6, which was purified by HPLC and hydrolyzed with Na-methoxide to produce 7. Results: Compound 2 (2a/2b) was obtained in 83% yield as a mixture of two anomeric products. Compound 3 was obtained from the 2a/2b mixture in 80% yield as one product. Coupling of 3 with ethylene glycol produced 4a in 90% yield. Compound 5 was obtained in 64% yield, and radiofluorination of 5 produced 6 in 62.5%±7.5% yields (n=8). Hydrolysis of 6 with Na-methoxide produced 7 in 42.0%±7.0% yield (n=8) from the end of bombardment. Conclusions: A simple 4-step synthesis of the precursor, compound 5, has been achieved with improved yields. A new formulation of [18 F]FEL has been developed that allows the product to remain stable at ambient temperature for use in animal studies. This improved synthesis of the precursor and stable formulation of [18 F]FEL should be useful for routine production of the radiotracer and its preclinical and, possibly, clinical applications. [Copyright &y& Elsevier]

Background The chemical composition of aerosols and particle size distributions are the most significant factors affecting air quality. In particular, the exposure to finer particles can cause short and long-term effects on human health. In the present paper PM10 (particulate matter with aerodynamic diameter lower than 10 μm), CO, NOx (NO and NO2), Benzene and Toluene trends monitored in six monitoring stations of Bari province are shown. The data set used was composed by bi-hourly means for all parameters (12 bi-hourly means per day for each parameter) and it's referred to the period of time from January 2005 and May 2007. The main aim of the paper is to provide a clear illustration of how large data sets from monitoring stations can give information about the number and nature of the pollutant sources, and mainly to assess the contribution of the traffic source to PM10 concentration level by using multivariate statistical techniques such as Principal Component Analysis (PCA) and Absolute Principal Component Scores (APCS). Results Comparing the night and day mean concentrations (per day) for each parameter it has been pointed out that there is a different night and day behavior for some parameters such as CO, Benzene and Toluene than PM10. This suggests that CO, Benzene and Toluene concentrations are mainly connected with transport systems, whereas PM10 is mostly influenced by different factors. The statistical techniques identified three recurrent sources, associated with vehicular traffic and particulate transport, covering over 90% of variance. The contemporaneous analysis of gas and PM10 has allowed underlining the differences between the sources of these pollutants. Conclusions The analysis of the pollutant trends from large data set and the application of multivariate statistical techniques such as PCA and APCS can give useful information about air quality and pollutant's sources. These knowledge can provide useful advices to environmental policies in order to reach the WHO recommended levels. [ABSTRACT FROM AUTHOR]

Abstract: Direct fluorination at the 2′-arabino-position of a pyrimidine nucleoside has been a long-standing challenge, yet we recently reported such a stereospecific fluorination for the first time in the synthesis of [18F]FMAU, albeit in low yields. Herein we report the results of an investigation on stereospecific fluorination on a variety of precursors for synthesis of [18F]FMAU. Several precursors were synthesized in multiple steps and fluorination was performed at the 2′-arabino-position using K[18F]/kryptofix 2.2.2. All precursors produced [18F]FMAU in low yields. [Copyright &y& Elsevier]

Abstract: Introduction: It is important to identify all circulating metabolites, including free fluoride, for accurate pharmacokinetic modeling of [18F]-labeled radiotracers. We sought to determine the most efficient method to detect and quantify low levels of free [18F]fluoride in biological samples. Methods: Low levels of [18F]fluoride were analyzed using two methods: (A) an ion-exchange cartridge and gamma counting, and (B) radio-HPLC, to compare the detection limits of these two analytical methods. Twenty microliters of [18F]fluoride solution was loaded onto an ion-exchange cartridge, then eluted with 20% MeCN/water (5 ml) and radioactivity trapped in the cartridge counted on a gamma counter. [18F]Fluoride was also determined in plasma and urine from mice injected with [18F]-labeled thymidine analogues using Method A. Results: The detection sensitivity of Method A was 9.4-fold higher than that of Method B (0.075±0.004 vs. 0.71±0.02 nCi). With Method A, [18F]fluoride was determined in plasma for [18F]FLT, [18F]FMAU, [18F]FEAU and N 3-[18F]FPrT as 1.4±0.31% (n=4), 0.17±0.49% (n=3), 4.88±1.62% (n=3) and 12.94±0.48% (n=4), respectively. The amount of [18F]fluoride determined in the urine was 11.49±1.60% (n=4) from [18F]FLT, 5.36±2.34% (n=3) from [18F]FMAU, 13.57±1.96% (n=3) from [18F]FEAU and 11.19±1.98% (n=4) from N 3-[18F]FPrT. Conclusion: Low levels of [18F]fluoride in biological samples can be detected and quantified using an ion-exchange cartridge and gamma counting. This methodology is simple, accurate and superior to the standard use of radio-HPLC on a C18 column for metabolite analysis, and it should be useful in pharmacokinetic modeling for animal imaging studies using an [18F]-labeled radiotracer and PET. [Copyright &y& Elsevier]

Adoptive transfer of antigen-specific cytotoxic T lymphocytes (CTLs) has been successfully used to treat patients with different types of cancer, However, the long-term spatial-temporal dynamics of the distribution of systemically infused CTLs remains largely unknown, Noninvasive imaging of adoptively transferred CTLs using molecular-genetic reporter imaging with positron emission tomography and computed tomography (PET-CT) represents an innovative approach to understanding the long-term migratory patterns and therapeutic potential of adoptively transferred T cells, Here we report the application of repetitive PET-CT imaging with [18F]fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil (18F-FEAU) in two nonhuman primates demonstrating that autologous polyclonal macaque T lymphocytes activated and transduced with a retroviral vector encoding for the sr39 mutant herpes simplex virus 1 thymidine kinase (sr39HSV1-tk) reporter gene can be detected after intravenous infusion in discrete lymphoid organs and in sites of inflammation, This study represents a proof of principle and supports the application of 18F-FEAU PET-CT imaging for monitoring the distribution of intravenously administered sr39HSV1-tk gene-transduced CTLs in humans. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The cannabinoid receptor type 2 (CB2) is an important target for development of drugs and imaging agents for diseases, such as neuroinflammation, neurodegeneration and cancer. Recently, we reported synthesis and results of in vitro receptor binding of a focused library of fluorinated 2-oxoquinoline derivatives as CB2 receptor ligands. Some of the compounds demonstrated to be good CB2-specific ligands with Ki values in the nanomolar to subnanomolar concentrations; therefore, we pursued the development of their 18F-labeled analogues that should be useful for positron emission tomography (PET) imaging of CB2 receptor expression. Here, we report the radiosynthesis of two 18F-labeled 2-oxoquinoline derivatives and the preliminary in vitro and ex vivo evaluation of one compound as a CB2-specific radioligand. Methods: 4-[18F]fluorobenzyl amine [18F]-3 was prepared by radiofluorination of 4-cyano-N,N,N-trimethylanilinium triflate salt followed by reduction with LiAlH4 and then coupled with acid chlorides 11 and 12 to afford [18F]-13 and [18F]-14. In vitro CB2 receptor binding assay was performed using U87 cells transduced with CB2 and CB1 receptor. Ex vivo autoradiography was performed with [18F]-14 on spleen and on CB2- and CB1-expressing and wild-type U87 subcutaneous tumors grown in mice. Results: The radiochemical yields of [18F]-13 and [18F]-14 were 10%–15.0% with an average of 12% (n=10); radiochemical purity was >99% with specific activity 1200 mCi/μmol. The dissociation constant Kd for [18F]-14 was 3.4 nM. Ex vivo autoradiography showed accumulation of [18F]-14 in the CB2-expressing tumor. Conclusion: Two new [18F]-labeled CB2 ligands have been synthesized. Compound [18F]-14 appears to be a potential PET imaging agent for the assessment of CB2 receptor expression; however, poor solubility restrain its use in vivo. [Copyright &y& Elsevier]

68 Ga-PSMA-11 is currently one of the most investigated PET agents for imaging both recurrent prostate cancer and relevant metastases; however, the production and distribution of 68 Ga-PSMA-11 is limited to a supply of only a few daily doses when using a commercially available 68 Ge/ 68 Ga generator. 68 Ge/ 68 Ga generators deliver only a modest amount of activity, up to 1850 MBq (50 mCi), when new, but it decreases with time. Additionally, the production of 68 Ga/ 68 Ge generators has not been able to meet the increasing demand of 68 Ga radiotracers. In response to the need for a more economically viable alternative, the focus of this study was to provide a simple and efficient method for producing 68 Ga-PSMA-11, using cyclotron-produced 68 Ga that is ready for routine clinical practice., (Published by Elsevier Ltd.)