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PET imaging AND vivo AND mouse

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18[F]FDG small animal PET study of sorafenib efficacy in lymphoma preclinical models.

Q J Nucl Med Mol Imaging. 2010 Jul 16;

Authors: Ambrosini V, Quarta C, Zinzani PL, Nanni C, Fini M, Torricelli P, Giavaresi G, D'errico-Grigioni A, Malvi D, Franchi R, Fanti S

AIM: Kinase inhibitors have been proposed as novel therapeutic agents in different forms of solid tumours. The Food and Drug Administration (FDA) approved the use of Sorafenib, an oral multikinase inhibitor, for advanced renal carcinoma and unresectable hepatocellular carcinoma. On-going studies are investigating the efficacy of Sorafenib in other solid tumours such as melanoma and non-small cells lung carcinoma and pre-clinical models showed the efficacy of treatment with Sorafenib in murine models of renal cells carcinoma, breast cancer, colon carcinoma and melanoma. To our knowledge, Sorafenib has never been employed in human lymphoma. The aim of the present study was to assess the efficacy of Sorafenib in murine models of human anaplastic large cells lymphoma (ALCL) and Hodgkin lymphoma (HD). METHODS: Sorafenib cytotoxicity was assessed in vitro and growth inhibition (IC50) was calculated. Cells were assayed for Caspase-3 to measure apoptosis. Human ALCL and HD xenografts in NOD/SCID mice were monitored by small animal positron emission tomography (PET) and computed tomography (CT) over time. Tumour bearing animals were randomly selected to receive treatment with Sorafenib or no treatment. Pathology was available in all cases. RESULTS: Sorafenib efficacy on cells proliferation and apoptosis (IC50: HD=0.0343mg/L; ALCL=0.319 mg/L) was confirmed in vitro. Caspase-3 production showed a dose-dependent trend reaching significantly higher values for 0.046mg/L and 0.465mg/L drug concentrations in both cell lines. In vivo experiments showed a progressive increase of tumour lesions metabolism and dimensions regardless treatment. CONCLUSION: Sorafenib showed a good citotoxic effect in vitro especially on human HD cell line, but these findings were not confirmed in vivo. The strong discrepancy between in vitro and in vivo results suggests that further studies are needed to better acknowledge the biodistribution and metabolism of Sorafenib in NOD/SCID mice. Factors influencing drug availability at tumour site or differences in the downstream pathways may be responsible for the scarse effect of treatment.

PMID: 20639808 [PubMed - as supplied by publisher]

Fluorine-18 labeled galactosylated chitosan for asialoglycoprotein-receptor-mediated hepatocyte imaging.

Bioorg Med Chem Lett. 2010 Jun 25;

Authors: Yang W, Mou T, Guo W, Jing H, Peng C, Zhang X, Ma Y, Liu B

Galactosylated chitosan (GC) was prepared by reacting lactobionic acid with water-soluble chitosan. GC was labeled with fluorine-18 by conjugation with N-succinimidyl-4-(18)F-fluorobenzoate ([(18)F]SFB) under a slightly basic condition. After rapid purification with HiTrap desalting column, [(18)F]FB-GC was obtained with high radiochemical purity (>97%) determined by radio-HPLC. The total reaction time for [(18)F]FB-GC was about 150min. Typical decay-corrected radiochemical yield was about 4-8%. Ex vivo biodistribution in normal mice showed that [(18)F]FB-GC had moderate activity accumulation in liver with very good retention (11.13+/-1.63, 10.97+/-1.90 and 10.77+/-0.95%ID/g at 10, 60, 120min after injection, respectively). The other tissues except kidney showed relative low radioactivity accumulation. The high liver/background ratio affords promising biological properties to get clear images. The specific binding of this radiotracer to the ASGP receptor was confirmed by blocking experiment in mice. Compared with the non-blocking group the hepatic uptake of [(18)F]FB-GC significantly declined in all selected time points. The better liver retention properties of [(18)F]FB-GC than that of albumin based imaging agents may improve imaging quality and simplify pharmacokinetic model of liver function in the future application with PET imaging.

PMID: 20634070 [PubMed - as supplied by publisher]

A Dual Radiologic Contrast Agent Protocol for (18)F-FDG and (18)F-FLT PET/CT Imaging of Mice Bearing Abdominal Tumors.

Mol Imaging Biol. 2010 Jul 15;

Authors: Aide N, Kinross K, Beauregard JM, Neels O, Potdevin T, Roselt P, Dorow D, Cullinane C, Hicks RJ

PURPOSE: The aim of the study was to improve abdominal tumor detection by use of a dual radiologic contrast protocol. PROCEDURES: eXia160(R) (Benitio international) was mixed with 2-deoxy-2-[(18)F]fluoro-D: -glucose or 3'-[(18)F]fluoro-3'-deoxythymidine for intravenous (IV) injections. Omnipaque(R) 300 (GE healthcare) was used for intraperitoneal (IP) injections. Positron emission tomography/computed tomography (PET/CT) scans were acquired on a Siemens Biograph(R) equipped with point spread function reconstruction. The optimal concentration and injection schedule of IP contrast agent was studied in 12 mice. The impact of IP contrast media on PET quantitative accuracy was investigated by phantom studies and by imaging six mice before and after IP injection of Omnipaque(R). The impact of a dual contrast media protocol on tumor delineation and quantitation was evaluated in 15 tumor-bearing mice using ex vivo counting as the reference. RESULTS: The optimal sequence was a mixture of tracer plus IV contrast agent followed by 1 mL of IP contrast agent (20 mg iodine/mL) administered 10 min before PET/CT acquisition. Phantom studies showed that the use of a 20-mg iodine/mL concentration of Omnipaque(R) led to a 4.8% overestimation of radioactivity concentration, as compared to saline. This was confirmed by animal studies that demonstrated a 4.3% overestimation. Tumor detection was excellent and correlation between PET/CT quantitative data and ex vivo counting was good (r (2) = 0.91, slope = 0.7). CONCLUSIONS: A dual radiologic contrast protocol is useful in PET/CT scanning of mice bearing abdominal tumors. Contrast agents used in this manner lead to a small but acceptable overestimation of quantitative PET data.

PMID: 20632117 [PubMed - as supplied by publisher]

Evaluation of Two Internalizing Carcinoembryonic Antigen Reporter Genes for Molecular Imaging.

Mol Imaging Biol. 2010 Jul 14;

Authors: Barat B, Kenanova VE, Olafsen T, Wu AM

PURPOSE: The objective of this article is to develop internalizing positron emission tomography (PET) reporter genes for tracking genetically modified T cells in vivo. PROCEDURES: The transmembrane and cytoplasmic domains of the human transferrin receptor (TfR) and CD5 were each fused to the carcinoembryonic (CEA) minigene N-A3 and expressed in Jurkat T cells. Internalization was evaluated by confocal microscopy or by intracellular uptake of (125)I-labeled anti-CEA scFv-Fc. Reporter gene-transfected Jurkat xenografts in mice were analyzed by immunohistochemistry (IHC) and imaged by PET using (124)I- or (64)Cu-scFv-Fc as tracers. RESULTS: Surface expression of TR(1-99)-NA3 was lower than that of NA3-CD5. Both reporter genes were internalized following binding of the anti-CEA antibody fragment. IHC of tumors showed strong staining of NA3-CD5, whereas TR(1-99)-NA3 stained weakly. Specific targeting of TR(1-99)-NA3 or NA3-CD5 was shown by PET in xenografted mice. CONCLUSIONS: The in vivo imaging studies suggest a potential application of the internalizing form of CEA (N-A3) as a PET reporter gene.

PMID: 20628903 [PubMed - as supplied by publisher]

Imaging of enzyme replacement therapy using PET.

Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10842-7

Authors: Phenix CP, Rempel BP, Colobong K, Doudet DJ, Adam MJ, Clarke LA, Withers SG

Direct enzyme replacement therapy (ERT) has been introduced as a means to treat a number of rare, complex genetic conditions associated with lysosomal dysfunction. Gaucher disease was the first for which this therapy was applied and remains the prototypical example. Although ERT using recombinant lysosomal enzymes has been shown to be effective in altering the clinical course of Gaucher disease, Fabry disease, Hurler syndrome, Hunter syndrome, Maroteaux-Lamy syndrome, and Pompe disease, the recalcitrance of certain disease manifestations underscores important unanswered questions related to dosing regimes, tissue half-life of the recombinant enzyme and the ability of intravenously administered enzyme to reach critical sites of known disease pathology. We have developed an innovative method for tagging acid beta-glucocerebrosidase (GCase), the recombinant enzyme formulated in Cerezyme(R) used to treat Gaucher disease, using an (18)F-labeled substrate analogue that becomes trapped within the active site of the enzyme. Using micro-PET we show that the tissue distribution of injected enzyme can be imaged in a murine model and that the PET data correlate with tissue (18)F counts. Further we show that PET imaging readily monitors pharmacokinetic changes effected by receptor blocking. The ability to (18)F-label GCase to monitor the enzyme distribution and tissue half-life in vivo by PET provides a powerful research tool with an immediate clinical application to Gaucher disease and a clear path for application to other ERTs.

PMID: 20534487 [PubMed - indexed for MEDLINE]

Cerenkov luminescence tomography for small-animal imaging.

Opt Lett. 2010 Apr 1;35(7):1109-11

Authors: Li C, Mitchell GS, Cherry SR

Cerenkov radiation is a well-known phenomenon in which optical photons are emitted by charged particles moving faster than the speed of light in a medium. We have observed Cerenkov photons emitted from beta-emitting radiotracers such as (18)F-fluorodeoxyglucose using a sensitive CCD camera. Phantom and in vivo mouse imaging experiments have demonstrated that surface measurements of the emitted Cerenkov optical photons could be used to reconstruct the radiotracer activity distribution inside an object by modeling the optical photon propagation with the diffusion equation and reconstructing the optical emission source distribution iteratively with a preconditioned conjugate gradient method.

PMID: 20364233 [PubMed - indexed for MEDLINE]

Synthesis and in vivo evaluation of [(11)C]tariquidar, a positron emission tomography radiotracer based on a third-generation P-glycoprotein inhibitor.

Bioorg Med Chem. 2010 Jun 22;

Authors: Bauer F, Kuntner C, Bankstahl JP, Wanek T, Bankstahl M, Stanek J, Mairinger S, Dörner B, Löscher W, Müller M, Erker T, Langer O

The aim of this study was to develop a positron emission tomography (PET) tracer based on the dual P-glycoprotein (P-gp) breast cancer resistance protein (BCRP) inhibitor tariquidar (1) to study the interaction of 1 with P-gp and BCRP in the blood-brain barrier (BBB) in vivo. O-Desmethyl-1 was synthesized and reacted with [(11)C]methyl triflate to afford [(11)C]-1. Small-animal PET imaging of [(11)C]-1 was performed in naïve rats, before and after administration of unlabeled 1 (15mg/kg, n=3) or the dual P-gp/BCRP inhibitor elacridar (5mg/kg, n=2), as well as in wild-type, Mdr1a/b((-/-)), Bcrp1((-/-)) and Mdr1a/b((-/-))Bcrp1((-/-)) mice (n=3). In vitro autoradiography was performed with [(11)C]-1 using brain sections of all four mouse types, with and without co-incubation with unlabeled 1 or elacridar (1muM). In PET experiments in rats, administration of unlabeled 1 or elacridar increased brain activity uptake by a factor of 3-4, whereas blood activity levels remained unchanged. In Mdr1a/b((-/-)), Bcrp1((-/-)) and Mdr1a/b((-/-))Bcrp1((-/-)) mice, brain-to-blood ratios of activity at 25min after tracer injection were 3.4, 1.8 and 14.5 times higher, respectively, as compared to wild-type animals. Autoradiography showed approximately 50% less [(11)C]-1 binding in transporter knockout mice compared to wild-type mice and significant displacement by unlabeled elacridar in wild-type and Mdr1a/b((-/-)) mouse brains. Our data suggest that [(11)C]-1 interacts specifically with P-gp and BCRP in the BBB. However, further investigations are needed to assess if [(11)C]-1 behaves in vivo as a transported or a non-transported inhibitor.

PMID: 20621487 [PubMed - as supplied by publisher]

PET imaging of fatty acid amide hydrolase in the brain: synthesis and biological evaluation of an (11)C-labelled URB597 analogue.

Nucl Med Biol. 2010 Jul;37(5):665-675

Authors: Wyffels L, Muccioli GG, Kapanda CN, Labar G, De Bruyne S, De Vos F, Lambert DM

INTRODUCTION: Fatty acid amide hydrolase (FAAH) is part of the endocannabinoid system (ECS) and has been linked to the aetiology of several neurological and neuropsychiatric disorders. So far no useful PET or SPECT tracer for in vivo visualisation of FAAH has been reported. We synthesized and evaluated a carbon-11-labeled URB597 analogue, biphenyl-3-yl [(11)C]-4-methoxyphenylcarbamate or [(11)C]-1, as potential FAAH imaging agent. METHODS: The inhibitory activity of 1 was determined in vitro using recombinant FAAH. Radiosynthesis of [(11)C]-1 was performed by methylation using [(11)C]-CH(3)I, followed by HPLC purification. Biological evaluation was done by biodistribution studies in wild-type and FAAH knock-out mice, and by ex vivo and in vivo metabolite analysis. The influence of URB597 pretreatment on the metabolisation profile was assessed. RESULTS: [(11)C]-1 was obtained in good yields and high radiochemical purity. Biodistribution studies revealed high brain uptake in wild-type and FAAH knock-out mice, but no retention of radioactivity could be demonstrated. Metabolite analysis and URB597 pretreatment confirmed the non-FAAH-mediated metabolisation of [(11)C]-1. The inhibition mechanism was determined to be reversible. In addition, the inhibition of URB597 appeared slowly reversible. CONCLUSIONS: Although [(11)C]-1 inhibits FAAH in vitro and displays high brain uptake, the inhibition mechanism seems to deviate from the proposed carbamylation mechanism. Consequently, it does not covalently bind to FAAH and will not be useful for mapping the enzyme in vivo. However, it represents a potential starting point for the development of in vivo FAAH imaging tools.

PMID: 20610171 [PubMed - as supplied by publisher]

Synthesis and in vivo evaluation of the putative breast cancer resistance protein inhibitor [(11)C]methyl 4-((4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl)phenyl)amino-carbonyl)-2-(quinoline-2-carbonylamino)benzoate.

Nucl Med Biol. 2010 Jul;37(5):637-644

Authors: Mairinger S, Langer O, Kuntner C, Wanek T, Bankstahl JP, Bankstahl M, Stanek J, Dörner B, Bauer F, Baumgartner C, Löscher W, Erker T, Müller M

INTRODUCTION: The multidrug efflux transporter breast cancer resistance protein (BCRP) is highly expressed in the blood-brain barrier (BBB), where it limits brain entry of a broad range of endogenous and exogenous substrates. Methyl is a recently discovered BCRP-selective inhibitor, which is structurally derived from the potent P-glycoprotein (P-gp) inhibitor tariquidar. The aim of this study was to develop a new PET tracer based on 1 to map BCRP expression levels in vivo. METHODS: Compound 1 was labelled with (11)C in its methyl ester function by reaction of the corresponding carboxylic acid 2 with [(11)C]methyl triflate. Positron emission tomography (PET) imaging of [(11)C]-1 was performed in wild-type, Mdr1a/b((-/-)), Bcrp1((-/-)) and Mdr1a/b((-/-))Bcrp1((-/-)) mice (n=3 per mouse type) and radiotracer metabolism was assessed in plasma and brain. RESULTS: Brain-to-plasma ratios of unchanged [(11)C]-1 were 4.8- and 10.3-fold higher in Mdr1a/b(()(-/-)()) and in Mdr1a/b(()(-/-)())Bcrp1(()(-/-)()) mice, respectively, as compared to wild-type animals, but only modestly increased in Bcrp1(()(-/-)()) mice. [(11)C]-1 was rapidly metabolized in vivo giving rise to a polar radiometabolite which was taken up into brain tissue. CONCLUSION: Our data suggest that [(11)C]-1 preferably interacts with P-gp rather than BCRP at the murine BBB which questions its reported in vitro BCRP selectivity. Consequently, [(11)C]-1 appears to be unsuitable as a PET tracer to map cerebral BCRP expression.

PMID: 20610168 [PubMed - as supplied by publisher]

Pre-clinical evaluation of a 3-nitro-1,2,4-triazole analogue of [(18)F]FMISO as hypoxia-selective tracer for PET.

Nucl Med Biol. 2010 Jul;37(5):565-575

Authors: Bejot R, Kersemans V, Kelly C, Carroll L, King RC, Gouverneur V

Hypoxia in solid tumours is associated with the promotion of various metabolic mechanisms and induces resistance to radio- and chemotherapy. Non-invasive positron emission tomography (PET) or single photon emission computed tomography by use of selective biomarkers has emerged as valuable tools for the detection of hypoxic areas within tumours so treatment can be modified accordingly. The aim of this investigation was to evaluate [(18)F]3-NTR, a 3-nitro-1,2,4-triazole analogue (N(1) substituted) of [(18)F]FMISO as a potential hypoxia selective tracer. 3-NTR and its (18)F-radiolabelled isotopic isomer were synthesised and compared with FMISO in vitro and in vivo. Their physicochemical properties were measured, the enzymatic reduction was evaluated, and the reactivity of their metabolites was investigated. Biodistribution and PET scans were performed on CBA mice bearing hypoxic CaNT tumour cells, using (18)F-labelled versions of the tracers. [(18)F]3-NTR uptake within hypoxic cells was lower than [(18)F]FMISO and [(18)F]3-NTR did not exhibit any better selectivity than FMISO as a PET tracer in vivo. Both (18)F-radiolabelled compounds are relatively evenly distributed within the whole body and the radioactive uptake within hypoxic tumours reaches a maximum at 30 min post injection and decreases thereafter. Xanthine oxidase exhibited a nitroreductase activity toward 3-NTR under anaerobic conditions, but reduced metabolites did not bind covalently. It is confirmed that 3-NTR is an electron acceptor. It is postulated that radiolabelled metabolites and fragments of [(18)F]3-NTR are freely diffusing due to their poor binding capacities. Thus [(18)F]3-NTR cannot be used as a hypoxia selective tracer for PET. The investigation provides insights into the importance of the propensity to form covalent adducts for such biomarkers.

PMID: 20610161 [PubMed - as supplied by publisher]

Kit formulation for (99m)Tc-labeling of recombinant anti-HER2 Affibody molecules with a C-terminally engineered cysteine.

Nucl Med Biol. 2010 Jul;37(5):539-546

Authors: Ahlgren S, Andersson K, Tolmachev V

INTRODUCTION: Molecular imaging of human epidermal growth factor receptor type 2 (HER2)-expression in malignant tumors provides potentially important information for patient management. Affibody molecules have shown to be suitable tracers for imaging applications using single photon emission computed tomography or positron emission tomography. Results from an earlier evaluation of the application of site-specific (99m)Tc-labeling of the Affibody molecule, Z(HER2:2395)-C, were favorable. METHODS: As a preparation for clinical application of this tracer, we have developed and evaluated a robust single-vial freeze-dried kit, allowing labeling of the Affibody molecule, Z(HER2:2395)-C, with (99m)Tc. RESULTS: The composition of the kit [containing glucoheptonate, EDTA and tin(II)-chloride], as well as the protein amount and the pertechnetate volume were optimized for a high labeling yield (>90%) and minimal presence of reduced hydrolyzed technetium colloids (<1%). The specificity to HER2 receptors, the binding competence and the stability in phosphate-buffered saline and murine serum were verified in vitro. The shelf-life was also evaluated in vitro, showing no reduction in labeling yield or binding capacity to HER2-expressing cells after over 400 days of storage of the single-vial freeze-dried kit. CONCLUSIONS: Z(HER2:2395)-C labeled with (99m)Tc using the lyophilized kit was stable and resulted in a favorable biodistribution in an in vivo evaluation in normal Naval Medical Research Institute mice.

PMID: 20610158 [PubMed - as supplied by publisher]

Synthesis and Ex Vivo Autoradiographic Evaluation of Ethyl-beta-D: -galactopyranosyl-(1,4')-2'-deoxy-2'-[(18)F]fluoro-beta-D: -glucopyranoside-A Novel Radioligand for Lactose-Binding Protein: Implications for Early Detection of Pancreatic Carcinomas with PET.

Mol Imaging Biol. 2010 Jul 1;

Authors: Ying Y, Ghosh P, Guo L, Pal A, Mukhapadhyay U, Peng Z, Yeh HH, Bertolini S, Flores LG, Young D, Volgin A, Soghomonyan S, Bornmann W, Logsdon C, Alauddin MM, Gelovani JG

INTRODUCTION: Previous studies demonstrated that the lactose-binding protein (hepatocellular carcinoma-intestine-pancreas and pancreatitis-associated proteins (HIP/PAP)) is upregulated >130 times in peritumoral pancreatic tissue as compared to normal pancreatic tissue. Therefore, we developed a new radiolabeled ligand of HIP/PAP, the ethyl-beta-D: -galactopyranosyl-(1,4')-2'-deoxy-2'-[(18)F]fluoro-beta-D: -glucopyranoside (Et-[(18)F]FDL) for noninvasive imaging of pancreatic carcinoma using positron emission tomography and computerized tomography (PET/CT). METHODS: The novel precursor and radiolabeling methods for synthesis of Et-[(18)F]FDL produced no isomers; the average decay-corrected radiochemical yield was 68%, radiochemical purity >99%, and specific activity >74 GBq/micromol. The radioligand properties of Et-[(18)F]FDL were evaluated using an ex vivo autoradiography and immunohistochemistry in pancreatic tissue sections obtained from mice-bearing orthotopic pancreatic tumor xenografts. RESULTS AND DISCUSSION: Et-[(18)F]FDL binding to peritumoral pancreatic tissue sections strongly correlated with HIP/PAP expression (r = 0.81) and could be completely blocked by treatment with 1 mM lactose. CONCLUSION: These results suggest that Et-[(18)F]FDL is a promising agent which should be evaluated for detection of early pancreatic carcinomas by PET/CT imaging.

PMID: 20593279 [PubMed - as supplied by publisher]

Radiolabeled 5-iodo-3'-O-(17beta-succinyl-5alpha-androstan-3-one)-2'-deoxyuridine and its 5'-monophosphate for imaging and therapy of androgen receptor-positive cancers: synthesis and biological evaluation.

J Med Chem. 2009 Aug 27;52(16):5124-43

Authors: Kortylewicz ZP, Nearman J, Baranowska-Kortylewicz J

High levels of androgen receptor (AR) are often indicative of recurrent, advanced, or metastatic cancers. These conditions are also characterized by a high proliferative fraction. 5-Radioiodo-3'-O-(17beta-succinyl-5alpha-androstan-3-one)-2'-deoxyuridine 8 and 5-radioiodo-3'-O-(17beta-succinyl-5alpha-androstan-3-one)-2'-deoxyuridin-5'-yl monophosphate 13 target AR. They are also degraded intracellularly to 5-radioiodo-2'-deoxyuridine 1 and its monophosphate 20, respectively, which can participate in the DNA synthesis. Both drugs were prepared at the no-carrier-added level. Precursors and methods are readily adaptable to radiolabeling with various radiohalides suitable for SPECT and PET imaging, as well as endoradiotherapy. In vitro and in vivo studies confirm the AR-dependent interactions. Both drugs bind to sex hormone binding globulin. This binding significantly improves their stability in serum. Biodistribution and imaging studies show preferential uptake and retention of 8 and 13 in ip xenografts of human ovarian adenocarcinoma cells NIH:OVCAR-3, which overexpress AR. When these drugs are administered at therapeutic dose levels, a significant tumor growth arrest is observed.

PMID: 19653647 [PubMed - indexed for MEDLINE]

Development and evaluation of a (68)Ga labeled pamoic acid derivative for in vivo visualization of necrosis using positron emission tomography.

Bioorg Med Chem. 2010 May 24;

Authors: Prinsen K, Li J, Vanbilloen H, Vermaelen P, Devos E, Mortelmans L, Bormans G, Ni Y, Verbruggen A

In this study, we labeled N,N'-bis(diethylenetriamine pentaacetic acid)-pamoic acid bis-hydrazide (bis-DTPA-PA) with the generator produced PET radionuclide gallium-68 and evaluated (68)Ga-bis-DTPA-PA as a potential tracer for in vivo visualization of necrosis by positron emission tomography (PET). Radiolabeling was achieved with a decay-corrected radiochemical yield of 63%. Biodistribution and in vivo stability studies in normal mice showed that (68)Ga-bis-DTPA-PA is cleared faster from normal tissue than the previously reported (99m)Tc(CO)(3) complex with bis-DTPA-PA which on the other hand is more stable in vivo. (68)Ga-bis-DTPA-PA showed a 3.5-5 times higher binding to necrotic tissue than to viable tissue as shown by in vitro autoradiography while no statistically significant increased hepatic uptake was found in a biodistribution study in a mouse model of hepatic apoptosis. Specificity and avidity for necrosis was further evaluated in rats with a reperfused partial liver infarction and ethanol induced muscular necrosis. Dynamic microPET images showed a fast and prolonged uptake of (68)Ga-bis-DTPA-PA in necrotic tissue with in vivo and ex vivo images correlating well with histochemical stainings. With necrotic to viable tissue activity ratios of 8-15 on ex vivo autoradiography, depending on the necrosis model, (68)Ga-bis-DTPA-PA showed a faster and higher uptake in necrotic tissue than the (99m)Tc(CO)(3) analog. These results show that (68)Ga-bis-DTPA-PA specifically binds to necrotic tissue and is a promising tracer for in vivo visualization of necrosis using PET.

PMID: 20580560 [PubMed - as supplied by publisher]

Synthesis and biological evaluation of [(18)F]tetrafluoroborate: a PET imaging agent for thyroid disease and reporter gene imaging of the sodium/iodide symporter.

Eur J Nucl Med Mol Imaging. 2010 Jun 25;

Authors: Jauregui-Osoro M, Sunassee K, Weeks AJ, Berry DJ, Paul RL, Cleij M, Banga JP, O'Doherty MJ, Marsden PK, Clarke SE, Ballinger JR, Szanda I, Cheng SY, Blower PJ

PURPOSE: The human sodium/iodide symporter (hNIS) is a well-established target in thyroid disease and reporter gene imaging using gamma emitters (123)I-iodide, (131)I-iodide and (99m)Tc-pertechnetate. However, no PET imaging agent is routinely available. The aim of this study was to prepare and evaluate (18)F-labelled tetrafluoroborate ([(18)F]TFB) for PET imaging of hNIS. METHODS: [(18)F]TFB was prepared by isotopic exchange of BF (4) (-) with [(18)F]fluoride in hot hydrochloric acid and purified using an alumina column. Its identity, purity and stability in serum were determined by HPLC, thin-layer chromatography (TLC) and mass spectrometry. Its interaction with NIS was assessed in vitro using FRTL-5 rat thyroid cells, with and without stimulation by thyroid-stimulating hormone (TSH), in the presence and absence of perchlorate. Biodistribution and PET imaging studies were performed using BALB/c mice, with and without perchlorate inhibition. RESULTS: [(18)F]TFB was readily prepared with specific activity of 10 GBq/mg. It showed rapid accumulation in FRTL-5 cells that was stimulated by TSH and inhibited by perchlorate, and rapid specific accumulation in vivo in thyroid (SUV = 72 after 1 h) and stomach that was inhibited 95% by perchlorate. CONCLUSION: [(18)F]TFB is an easily prepared PET imaging agent for rodent NIS and should be evaluated for hNIS PET imaging in humans.

PMID: 20577737 [PubMed - as supplied by publisher]

Preparation, biological evaluation, and pharmacokinetics of the human anti-HER1 monoclonal antibody panitumumab labeled with 86Y for quantitative PET of carcinoma.

J Nucl Med. 2010 Jun;51(6):942-50

Authors: Nayak TK, Garmestani K, Baidoo KE, Milenic DE, Brechbiel MW

Panitumumab, a human monoclonal antibody that binds to the epidermal growth factor receptor (HER1), was approved by the Food and Drug Administration in 2006 for the treatment of patients with HER1-expressing carcinoma. In this article, we describe the preclinical development of (86)Y-CHX-A''-diethylenetriaminepentaacetic acid (DTPA)-panitumumab for quantitative PET of HER1-expressing carcinoma. Panitumumab was conjugated to CHX-A''-DTPA and radiolabeled with (86)Y. In vivo biodistribution, PET, blood clearance, area under the curve, area under the moment curve, and mean residence time were determined for mice bearing HER1-expressing human colorectal (LS-174T), prostate (PC-3), and epidermoid (A431) tumor xenografts. Receptor specificity was demonstrated by coinjection of 0.1 mg of panitumumab with the radioimmunoconjugate. RESULTS: (86)Y-CHX-A''-DTPA-panitumumab was routinely prepared with a specific activity exceeding 2 GBq/mg. Biodistribution and PET studies demonstrated a high HER1-specific tumor uptake of the radioimmunoconjugate. In mice bearing LS-174T, PC-3, or A431 tumors, the tumor uptake at 3 d was 34.6 +/- 5.9, 22.1 +/- 1.9, and 22.7 +/- 1.7 percentage injected dose per gram (%ID/g), respectively. The corresponding tumor uptake in mice coinjected with 0.1 mg of panitumumab was 9.3 +/- 1.5, 8.8 +/- 0.9, and 10.0 +/- 1.3 %ID/g, respectively, at the same time point, demonstrating specific blockage of the receptor. Normal organ and tumor uptake quantified by PET was closely related (r(2) = 0.95) to values determined by biodistribution studies. The LS-174T tumor had the highest area under the curve (96.8 +/- 5.6 %ID d g(-1)) and area under the moment curve (262.5 +/- 14.9 %ID d(2) g(-1)); however, the tumor mean residence times were identical for all 3 tumors (2.7-2.8 d). CONCLUSION: This study demonstrates the potential of (86)Y-CHX-A''-DTPA-panitumumab for quantitative noninvasive PET of HER1-expressing tumors and represents the first step toward clinical translation.

PMID: 20484421 [PubMed - indexed for MEDLINE]

D2 dopamine receptor internalization prolongs the decrease of radioligand binding after amphetamine: a PET study in a receptor internalization-deficient mouse model.

Neuroimage. 2010 May 1;50(4):1402-7

Authors: Skinbjerg M, Liow JS, Seneca N, Hong J, Lu S, Thorsell A, Heilig M, Pike VW, Halldin C, Sibley DR, Innis RB

Dopamine released by amphetamine decreases the in vivo binding of PET radioligands to the dopamine D(2) receptor. Although concentrations of extracellular dopamine largely return to baseline within 1 to 2 h after amphetamine treatment, radioligand binding remains decreased for several hours. The purpose of this study was to determine whether the prolonged decrease of radioligand binding after amphetamine administration is caused by receptor internalization. To distinguish dopamine displacement from receptor internalization, we used wild-type and arrestin3 (arr3) knockout mice, which are incapable of internalizing D(2) receptors. In addition, we used both the D(2) selective agonist [(11)C]MNPA (which is thought to bind to the high affinity state of the receptor) and the D(2) selective antagonist [(18)F]fallypride (which does not differentiate between high and low affinity state). After an initial baseline scan, animals were divided in three groups for a second scan: either 30 min or 4 h after amphetamine administration (3 mg/kg, i.p.) or as retest. At 30 min, [(11)C]MNPA showed greater displacement than [(18)F]fallypride, but each radioligand gave similar displacement in knockout and wild-type mice. At 4 h, the binding of both radioligands returned to baseline in arr3 knockout mice, but remained decreased in wild-type mice. Radioligand binding was unaltered on retest scanning. Our results suggest that the prolonged decrease of radioligand binding after amphetamine is mainly due to internalization of the D(2) receptor rather than dopamine displacement. In addition, this study demonstrates the utility of small animal PET to study receptor trafficking in vivo in genetically modified mice.

PMID: 20097293 [PubMed - indexed for MEDLINE]

[(18)F]FLT PET for Non-Invasive Monitoring of Early Response to Gene Therapy in Experimental Gliomas.

Mol Imaging Biol. 2010 Jun 19;

Authors: Rueger MA, Ameli M, Li H, Winkeler A, Rueckriem B, Vollmar S, Galldiks N, Hesselmann V, Fraefel C, Wienhard K, Heiss WD, Jacobs AH

The purpose of this study was to investigate the potential of 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) positron emission tomography (PET) to detect early treatment responses in gliomas. Human glioma cells were stably transduced with genes yielding therapeutic activity, sorted for different levels of exogenous gene expression, and implanted subcutaneously into nude mice. Multimodality imaging during prodrug therapy included (a) magnetic resonance imaging, (b) PET with 9-(4-[(18)F]fluoro-3-hydroxymethylbutyl)guanine assessing exogenous gene expression, and (c) repeat [(18)F]FLT PET assessing antiproliferative therapeutic response. All stably transduced gliomas responded to therapy with significant reduction in tumor volume and [(18)F]FLT accumulation within 3 days after initiation of therapy. The change in [(18)F]FLT uptake before and after treatment correlated to volumetrically calculated growth rates. Therapeutic efficacy as monitored by [(18)F]FLT PET correlated to levels of therapeutic gene expression measured in vivo. Thus, [(18)F]FLT PET assesses early antiproliferative effects, making it a promising radiotracer for the development of novel treatments for glioma.

PMID: 20563754 [PubMed - as supplied by publisher]

PET probes for distinct metabolic pathways have different cell specificities during immune responses in mice.

J Clin Invest. 2010 Jun 1;120(6):2005-15

Authors: Nair-Gill E, Wiltzius SM, Wei XX, Cheng D, Riedinger M, Radu CG, Witte ON

Clinical tools that measure changes in immune cell metabolism would improve the diagnosis and treatment of immune dysfunction. PET, utilizing probes for specific metabolic processes, detects regions of immune activation in vivo. In this study we investigated the immune cell specificity of PET probes for two different metabolic pathways: [18F]-2-fluorodeoxyglucose ([18F]-FDG) for glycolysis and [18F]-2-fluoro-D-(arabinofuranosyl)cytosine ([18F]-FAC) for deoxycytidine salvage. We isolated innate and adaptive immune cells from tissues of mice challenged with a retrovirus-induced sarcoma and measured their ability to accumulate FDG and FAC. We determined that the two probes had distinct patterns of accumulation: FDG accumulated to the highest levels in innate immune cells, while FAC accumulated predominantly in CD8+ T cells in a manner that correlated with cellular proliferation. This study demonstrates that innate and adaptive cell types differ in glycolytic and deoxycytidine salvage demands during an immune response and that these differential metabolic requirements can be detected with specific PET probes. Our findings have implications for the interpretation of clinical PET scans that use [18F]-FDG or [18F]-FAC to assess immune function in vivo and suggest potential applications of metabolic PET to monitor the effects of targeted immune modulation.

PMID: 20484820 [PubMed - indexed for MEDLINE]