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Kengo Sato

Publications and source records attributed to Kengo Sato.

15 recordsLinked to original sources
PubMed2006

Presence of immunoreactive salusin-alpha in human serum and urine.

Salusins, identified from a full-length enriched human cDNA library by bioinformatics analyses, show mitogenic, neuromodulatory and hemodynamic activities in rats. They are expressed in a wide variety of human tissues, but their precise structures and levels in human body fluids remain unknown. We developed a radioimmunoassay suitable for the detection of immunoreactive human salusin-alpha and characterized the molecular forms and concentrations of salusin-alpha in human serum and urine. The assay allowed for measurement of immunoreactive salusin-alpha concentrations as low as 1 fmol/tube after extraction of serum with an octyl-silica column, and the concentration required for 50% inhibition of binding was 40 fmol/tube. Cross-reactivities with salusin-beta and other bioactive peptides were negligible. Salusin-alpha-like immunoreactivity in normal human serum and urine ranged from 11.0 to 40.4 pmol/l (mean+/-S.D., 23.3+/-8.1 pmol/l, n=31) and from 18.6 to 367.3 pmol/l (mean+/-S.D., 156.8+/-95.8 pmol/l), respectively. Reverse-phase high performance liquid chromatography coupled with radioimmunoassay detection revealed a major immunoreactive component that coeluted with authentic salusin-alpha. These data indicate the presence of salusin-alpha in human serum and urine, thereby verifying the initially predicted processing sites for salusin-alpha in humans.

Adult↗
PubMed2006

Evaluation of D-isomers of O-18F-fluoromethyl, O-18F-fluoroethyl and O-18F-fluoropropyl tyrosine as tumour imaging agents in mice.

The aim of this study was to evaluate the properties of the D-amino acid isomers O-(18)F-fluoromethyl tyrosine ((18)F-FMT), O-(18)F-fluoroethyl tyrosine ((18)F-FET) and O-(18)F-fluoropropyl tyrosine ((18)F-FPT) as tumour-detecting agents with PET in comparison with the corresponding L-isomers. L- or D-(18)F-FMT, (18)F-FET or (18)F-FPT, prepared by (18)F-fluoromethylation, (18)F-fluoroethylation or (18)F-fluoropropylation of L- and D-tyrosine, was intravenously injected into BALB/cA Jcl-nu mice bearing HeLa tumour cells. At 5, 15, 30 and 60 min post intravenous administration, the uptake of each compound in normal abdominal organs and xenotransplanted HeLa cells was determined using the tissue dissection method. Metabolic stability analyses of these compounds in the plasma were performed with the thin-layer chromatography method. In the plasma fraction, although L- and D-isomers of (18)F-FMT, (18)F-FET and (18)F-FPT provided comparable metabolic stability, D-isomers of these labelled compounds revealed a faster elimination rate than their L-isomers, with a higher peak uptake in the blood and kidney 5 min post administration. Compared with natural amino acid ligands, such as L-(11)C-methionine, the uptake of L-isomers of these labelled compounds was relatively low and stable in the abdominal organs, while D-isomers revealed much lower and faster clearance rates compared with the corresponding L-isomers. Among the abdominal organs, the pancreas showed relatively high uptake of all the labelled compounds used here, and the uptake of D-isomers was much lower than that of the L-isomers. Although tumour uptake levels of D-isomers of (18)F-FMT, (18)F-FET and (18)F-FPT were almost 95%, 43% and 39% of the uptake levels of each of the L-isomers 60 min post administration, the tumour-to-blood ratios of these D-isomers were 181%, 137% and 101% of the ratios of the corresponding L-isomers. D-isomers of (18)F-FMT and (18)F-FET indicated improved tumour-to-liver ratios compared with the corresponding L-isomers, and D-(18)F-FPT showed the highest tumour-to-pancreas ratio among all the other compounds assayed here. These results suggest that D-isomers of (18)F-fluoroalkyl tyrosine analogues are potential tracers for tumour imaging with PET.

Animals↗
PubMed2006

Evaluation of D-isomers of O-11C-methyl tyrosine and O-18F-fluoromethyl tyrosine as tumor-imaging agents in tumor-bearing mice: comparison with L- and D-11C-methionine.

UNLABELLED: The aim of this study was to investigate whether D-amino acid isomers of O-(11)C-methyl tyrosine ((11)C-CMT) and O-(18)F-fluoromethyl tyrosine ((18)F-FMT) were better than the corresponding L-isomers as tumor- detecting agents with PET in comparison with the difference between L- and D-methyl-(11)C-methionine ((11)C-MET). METHODS: L- and D-(11)C-MET, (11)C-CMT, and (18)F-FMT were injected intravenously into BALB/cA Jcl-nu mice bearing HeLa tumor cells. At 5, 15, 30, and 60 min after injection, normal abdominal organs and xenotransplanted HeLa cells were sampled, and the uptake of each ligand was determined. Metabolic analyses of these compounds in the plasma were also performed. Accumulation of the d-isomers of (11)C-MET, (11)C-CMT, and (18)F-FMT in turpentine-induced inflammatory tissue was assayed in comparison with (18)F-FDG. The whole-body distribution of each tracer was imaged with a planar positron imaging system (PPIS). RESULTS: Although the tumor uptake (standardized uptake value [SUV]) levels of the D-isomers of (11)C-MET, (11)C-CMT, and (18)F-FMT were 261%, 72%, and 95% of each L-isomer 60 min after administration, the tumor-to-blood ratios of these D-isomers were 130%, 140%, and 182% of the corresponding L-isomers. In the blood, the D-isomers of these labeled compounds revealed a relatively faster elimination rate compared with their L-isomers, with a high peak uptake in the blood and kidney 5 min after administration. Compared with the natural amino acid ligand l-(11)C-MET, the uptake of L-isomers of (11)C-CMT and (18)F-FMT was relatively low and stable in the abdominal organs, whereas D-isomers revealed much lower levels and faster clearance rates compared with corresponding L-isomers. Among the abdominal organs, the pancreas showed a relatively high uptake of (11)C-CMT and (18)F-FMT; the uptake of these D-isomers was much lower than that of L-isomers. Pretreatment with cycloheximide, a protein synthesis inhibitor, resulted in a marked reduction of L-(11)C-MET uptake and a slight reduction of D-(11)C-MET uptake into protein fractions, whereas no significant changes were detected with L- and D-(11)C-CMT and (18)F-FMT. D-Isomers of (11)C-MET, (11)C-CMT, and (18)F-FMT did not accumulate in turpentine-induced inflammatory tissue, where (18)F-FDG revealed a high uptake. Whole-body imaging with a PPIS provided consistent distribution data obtained from the tissue dissection analysis. CONCLUSION: These results suggest that D-isomers of (11)C-CMT and (18)F-FMT could be potentially better tracers than L- and D-(11)C-MET for tumor imaging with PET.

Animals↗
PubMed2005

An in vitro Shwartzman reaction-like response is augmented age-dependently in human peripheral blood mononuclear cells.

A lethal human septic shock model, mouse generalized Shwartzman reaction (GSR), was elicited by two consecutive lippolysaccharide (LPS) injections (24 h apart) in which interferon-gamma (IFN-gamma) induced by interleukin (IL)-12 played a critical role in the priming phase, and tumor necrosis factor (TNF) was an important effector molecule in the second phase. We recently reported IL-12/LPS-induced mouse GSR age-dependently enhanced. We herein demonstrate that human peripheral blood mononuclear cells (PBMC) from healthy adults/elderly, cultured with IL-12 for 24 h and with LPS for an additional 24 h, produced a much larger amount of TNF (which increased age-dependently) than did PBMC without IL-12 priming. Whereas macrophages mainly produced TNF following LPS stimulation, macrophages and lymphocytes were necessary for a sufficient TNF production. IL-12-induced IFN-gamma up-regulated Toll-like receptor 4 (TLR-4) on macrophages of adults. Although the PBMC from children produced a substantial amount of IFN-gamma after IL-12 priming, the GSR response, with augmented TNF production and an up-regulated TLR-4 expression of macrophages, was not elicited by LPS stimulation. CD56+natural killer cells, CD56+T cells, and CD57+T cells (NK-T cells), which age-dependently increased in PBMC, produced much larger amounts of IFN-gamma after IL-12 priming than that of conventional CD56-CD57-T cells and also induced cocultured macrophages to produce TNF by subsequent LPS stimulation. The elder septic patients were consistently more susceptible to lethal shock with enhanced serum TNF levels than the adult patients. The NK cells, NK-T cells, and macrophages, which change proportionally or functionally with aging, might be involved in the enhanced GSR response/septic shock observed in elderly patients.

Adult↗
PubMed2005

RNA secondary structural alignment with conditional random fields.

MOTIVATION: The computational identification of non-coding RNA regions on the genome is currently receiving much attention. However, it is essentially harder than gene-finding problems for protein-coding regions because non-coding RNA sequences do not have strong statistical signals. Since comparative sequence analysis is effective for non-coding RNA detection, efficient computational methods are expected for structural alignment of RNA sequences. Several methods have been proposed to accomplish the structural alignment tasks for RNA sequences, and we found that one of the most important points is to estimate an accurate score matrix for calculating structural alignments. RESULTS: We propose a novel approach for RNA structural alignment based on conditional random fields (CRFs). Our approach has some specific features compared with previous methods in the sense that the parameters for structural alignment are estimated such that the model can most probably discriminate between correct alignments and incorrect alignments, and has the generalization ability so that a satisfiable score matrix can be obtained even with a small number of sample data without overfitting. Experimental results clearly show that the parameter estimation with CRFs can outperform all the other existing methods for structural alignments of RNA sequences. Furthermore, structural alignment search based on CRFs is more accurate for predicting non-coding RNA regions than the other scoring methods. These experimental results strongly support our discriminative method employing CRFs to estimate the score matrix parameters. AVAILABILITY: The program which is implemented in C++ is available at http://phmmts.dna.bio.keio.ac.jp/ under the GNU public license.

Base Sequence↗
PubMed2005

Pair stochastic tree adjoining grammars for aligning and predicting pseudoknot RNA structures.

MOTIVATION: Since the whole genome sequences of many species have been determined, computational prediction of RNA secondary structures and computational identification of those non-coding RNA regions by comparative genomics become important. Therefore, more advanced alignment methods are required. Recently, an approach of structural alignment for RNA sequences has been introduced to solve these problems. Pair hidden Markov models on tree structures (PHMMTSs) proposed by Sakakibara are efficient automata-theoretic models for structural alignment of RNA secondary structures, although PHMMTSs are incapable of handling pseudoknots. On the other hand, tree adjoining grammars (TAGs), a subclass of context-sensitive grammars, are suitable for modeling pseudoknots. Our goal is to extend PHMMTSs by incorporating TAGs to be able to handle pseudoknots. RESULTS: We propose pair stochastic TAGs (PSTAGs) for aligning and predicting RNA secondary structures including a simple type of pseudoknot which can represent most known pseudoknot structures. First, we extend PHMMTSs defined on alignment of 'trees' to PSTAGs defined on alignment of 'TAG trees' which represent derivation processes of TAGs and are functionally equivalent to derived trees of TAGs. Then, we develop an efficient dynamic programming algorithm of PSTAGs for obtaining an optimal structural alignment including pseudoknots. We implement the PSTAG algorithm and demonstrate the properties of the algorithm by using it to align and predict several small pseudoknot structures. We believe that our implemented program based on PSTAGs is the first grammar-based and practically executable software for comparative analyses of RNA pseudoknot structures, and, further, non-coding RNAs.

Algorithms↗
PubMed2005

Critical role of the liver CD8+ CD122+ T cells in the generalized Shwartzman reaction of mice.

We examined the role of mouse CD8+ CD122+ T cells, which increase in number with age, in the generalized Shwartzman reaction. This reaction was induced by IL-12 priming and subsequent LPS challenge (after 24 h) in mice of various ages (4-50 weeks of age). Although most young mice (4 or 6 weeks of age) survived, mortality essentially increased with increasing age of the mice, and all mice of 20 weeks of age or older died within 48 h. Serum TNF-alpha levels after LPS challenge also increased age dependently. The neutralization of either IL-12-induced IFN-gamma or LPS-induced TNF-alpha improved the survival of middle-aged (25-week-old) mice. Both IFN-gamma production after IL-12 priming and TNF-alpha production from the liver mononuclear cells after LPS challenge were also prominent in the middle-aged mice. CD8+CD122+ T cells cultured with IL-12 produced a much larger amount of IFN-gamma than CD8+CD122- T cells. Although the depletion of NK/NK T cells did not decrease the IFN-gamma or TNF-alpha production in the Shwartzman reaction of the middle-aged mice, an additional depletion of CD8+CD122+ T cells did decrease such production and also improved mouse survival. Furthermore, young mice transferred with CD8+CD122+ T cells from aged B6 nude mice showed an enhanced Shwartzman reaction.

Age Factors↗
PubMed2005

Chronic NMDA antagonism impairs working memory, decreases extracellular dopamine, and increases D1 receptor binding in prefrontal cortex of conscious monkeys.

This study demonstrates that dizocilpine (MK-801), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, impairs working memory of conscious behaving monkeys. In addition, acute and chronic MK-801 produces different effects on D(1) and D(2) receptor binding in prefrontal cortex (PFC). Extrastriatal neocortical receptor D(1) (D(1)R) and D(2) (D(2)R) binding were assayed by [(11)C]NNC112 and [(11)C]FLB457, respectively, using high-specific radioactivity and a specially designed monkey positron emission tomograph (PET). Acute single dose (0.03, 0.1, and 0.3 mg/kg) i.v. administration of MK-801 resulted in dose-related impairment of working memory performance of an oculomotor delayed response (ODR) task. There was no impairment of performance of a visually guided saccade (VGS) task with low doses of 0.03 and 0.1, but it was depressed with 0.3 mg/kg. Chronic daily MK-801 (0.03 mg/kg, i.m., b.i.d. for 13 days) induced impaired ODR task performance with no effect on the VGS task. Although acute single doses of MK-801 caused no significant changes in [(11)C]NNC112 binding to PFC D(1)R, chronic daily treatment increased binding about 14% (P<.05). Acute MK-801 dose-dependently decreased [(11)C]FLB457 binding about 35% (P<.01) to PFC D(2)R; chronic treatment had no significant effect. Microdialysis analyses demonstrated that acute single doses of MK-801 (0.03 and 0.1 mg/kg) increased extracellular glutamate and dopamine (DA) levels in PFC. Chronic MK-801 gradually lowered glutamate and DA levels in PFC. The results demonstrate in conscious, unanesthetized primates that MK-801 induces impairment of PFC function, as measured by working memory performance. Furthermore, in response to lowered levels of DA in PFC, D(1)R binding is increased, whereas D(2)R binding is not.

Animals↗
PubMed2004

Effects of acute acetylcholinesterase inhibition on the cerebral cholinergic neuronal system and cognitive function: Functional imaging of the conscious monkey brain using animal PET in combination with microdialysis.

This study demonstrated the effects of acute acetylcholinesterase (AChE) inhibition by donepezil (Aricept) on the cerebral cholinergic neuronal system in the brains of young (5.2 +/- 1.1 years old) and aged (20.3 +/- 2.6 years old) monkeys (Macaca mulatta) in the conscious state. Donepezil at doses of 50 and 250 microg/kg suppressed AChE activity, analyzed by metabolic rate (k(3)) of N-[(11)C]methyl-4-piperidyl acetate ([(11)C]MP4A), in all cortical regions in a dose-dependent manner in both age groups. However, the suppression degree was more marked in young than in aged monkeys. AChE inhibition by donepezil resulted in a dose-dependent increase in acetylcholine levels in the prefrontal cortex of young animals as measured by microdialysis. Binding of (+)N-[(11)C]propyl-3-piperidyl benzilate ([(11)C](+)3-PPB) to cortical muscarinic receptors was reduced by donepezil, probably in a competitive inhibition manner. Aged monkeys showed less reduction of [(11)C](+)3-PPB binding than young animals. As evaluated by an oculomotor delayed response task, aged monkeys showed impaired working memory performance compared to young monkeys, and the impaired performance was partly improved by the administration of donepezil, due to the facilitation of the cholinergic neuronal system by AChE inhibition. These results demonstrate that the PET imaging technique with specific labeled compounds in combination with microdialysis and a behavioral cognition task could be a useful method to clarify the mechanism of drugs in the living brains of experimental animals.

Aging↗
PubMed2004

Transient focal ischemia affects the cAMP second messenger system and coupled dopamine D1 and 5-HT1A receptors in the living monkey brain: a positron emission tomography study using microdialysis.

Using positron emission tomography (PET) and microdialysis, the present study showed that neuronal damages after transient focal ischemia was partly induced by hyperactivation of the cyclic adenosine 3',5'-monophosphate (cAMP) second messenger system through modulations of dopamine D, and serotonin 5-HT1A receptors in the living brains of cynomolgus monkeys. Occlusion of the right middle cerebral artery for 3 hours suppressed CBF in the striatum, and reperfusion induced hyperperfusion in the neocortex and striatum of the occluded side. Six hours after reperfusion, the activity of the cAMP second messenger system assayed with [11C]rolipram was significantly facilitated in the neocortex and striatum where CBF was lowered more than 40% of normal during occlusion ("ischemic" area). Seven days later, impaired dopamine D1 and 5-HT1A receptor binding, measured with [11C]SCH23390 and [carbonyl-11C]WAY-100635, respectively, was observed in the ischemic area. Microdialysis analysis revealed that the striatal dopamine level provided a transient and marked increased during occlusion and after reperfusion, whereas the cortical serotonin level transiently increased only after reperfusion, and was at an undetectable level thereafter. Administration of rolipram (0.1 and 1 mg/kg, intravenously) during occlusion facilitated reduction of dopamine D1 binding, whereas rolipram administration 6 hours after reperfusion induced a further decrease in 5-HT1A receptor binding. These results suggest that the activation of cAMP second messenger system modulated by dopamine D1 and 5-HT1A receptors could be involved in the neuronal degeneration after transient cerebral ischemic insult.

Animals↗
PubMed2004

Evaluation of 3'-deoxy-3'-18F-fluorothymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice.

UNLABELLED: 3'-Deoxy-3'-18F-fluorothymidine (18F-FLT) has been suggested as a new PET tracer for imaging tumor proliferation. We investigated the use of 18F-FLT to monitor the response of tumors to radiotherapy and photodynamic therapy (PDT) in mice. METHODS: C3H/He mice bearing an SCCVII tumor were treated with single-dose x-ray irradiation of 20 Gy. Tumor uptake was examined for 18F-FLT, 3H-thymidine (3H-Thd), 18F-FDG, and 14C-deoxyglucose (14C-DG) at 6 h, 12 h, 24 h, 3 d, and 7 d after radiotherapy. BALB/c nu/nu mice bearing a HeLa tumor were treated with PDT. Tumor uptake was examined for the 4 tracers at 24 h after PDT. Expression of proliferating cell nuclear antigen (PCNA) was determined in untreated and treated tumors. RESULTS: In the biodistribution study, considerable uptake of 18F-FLT was observed in both tumor types. Tumor volumes decreased to 39.3% +/- 22.4% at 7 d after radiotherapy. The PCNA labeling index was reduced in x-ray-irradiated tumors (control, 53.2% +/- 8.7%; 6 h, 38.5% +/- 5.3%; 24 h after radiotherapy, 36.8% +/- 5.3%). 18F-FLT uptake in tumor expressed as the percentage of the injected dose per gram of tumor (%ID/g) decreased significantly at 6 h and remained low until 3 d after radiotherapy (control, 9.7 +/- 1.2 %ID/g; 6 h, 5.9 +/- 0.4 %ID/g; 24 h, 6.1 +/- 1.3 %ID/g; 3 d after radiotherapy, 6.4 +/- 1.1 %ID/g). 18F-FDG uptake tended to gradually decrease but a significant decrease was found only at 3 d (control, 12.1 +/- 2.7 %ID/g; 6 h, 13.3 +/- 2.3 %ID/g; 24 h, 8.6 +/- 1.8 %ID/g; 3 d after radiotherapy, 6.9 +/- 1.2 %ID/g). PDT resulted in a reduction of the PCNA labeling index (control, 82.0% +/- 8.6%; 24 h after PDT, 13.5% +/- 12.7%). Tumor uptake of 18F-FLT decreased (control, 11.1 +/- 1.3 %ID/g; 24 h after PDT, 4.0 +/- 2.2 %ID/g), whereas 18F-FDG uptake did not decrease significantly after PDT (control, 3.5 +/- 0.6 %ID/g; 24 h after PDT, 2.3 +/- 1.1 %ID/g). Changes in the uptake of 18F-FLT and 18F-FDG were similar to those of 3H-Thd and 14C-DG, respectively. CONCLUSION: In our model system, changes in 18F-FLT uptake after radiotherapy and PDT were correlated with those of 3H-Thd and the PCNA labeling index. The decrease in 18F-FLT uptake after treatments was more rapid or pronounced than that of 18F-FDG. Therefore, 18F-FLT may be a feasible PET tracer for monitoring response to therapy in oncology.

Animals↗
PubMed2004

Pair stochastic tree adjoining grammars for aligning and predicting pseudoknot RNA structures.

MOTIVATION: Since the whole genome sequences for many species are currently available, computational predictions of RNA secondary structures and computational identifications of those non-coding RNA regions by comparative genomics become important, and require more advanced alignment methods. Recently, an approach of structural alignments for RNA sequences has been introduced to solve these problems. By structural alignments, we mean a pairwise alignment to align an unfolded RNA sequence into a folded RNA sequence of known secondary structure. Pair HMMs on tree structures (PHMMTSs) proposed by Sakakibara are efficient automata-theoretic models for structural alignments of RNA secondary structures, but are incapable of handling pseudoknots. On the other hand, tree adjoining grammars (TAGs) is a subclass of context-sensitive grammar, which is suitable for modeling pseudoknots. Our goal is to extend PHMMTSs by incorporating TAGs to be able to handle pseudoknots. RESULTS: We propose the pair stochastic tree adjoining grammars (PSTAGs) for modeling RNA secondary structures including pseudoknots and show the strong experimental evidences that modeling pseudoknot structures significantly improves the prediction accuracies of RNA secondary structures. First, we extend the notion of PHMMTSs defined on alignments of 'trees' to PSTAGs defined on alignments of "TAG (derivation) trees", which represent a top-down parsing process of TAGs and are functionally equivalent to derived trees of TAGs. Second, we modify PSTAGs so that it takes as input a pair of a linear sequence and a TAG tree representing a pseudoknot structure of RNA to produce a structural alignment. Then, we develop a polynomial-time algorithm for obtaining an optimal structural alignment by PSTAGs, based on dynamic programming parser. We have done several computational experiments for predicting pseudoknots by PSTAGs, and our computational experiments suggests that prediction of RNA pseudoknot structures by our method are more efficient and biologically plausible than by other conventional methods. The binary code for PSTAG method is freely available from our website at http://www.dna.bio.keio.ac.jp/pstag/.

Algorithms↗
PubMed2002

Age differences in phosphodiesterase type-IV and its functional response to dopamine D1 receptor modulation in the living brain: a PET study in conscious monkeys.

The present study demonstrated the age-related changes in the striatal dopamine D1 receptor binding and its related cAMP second-messenger system in the living brains of conscious young (6.4 +/- 1.8 years old) and aged (19.5 +/- 3.3 years old) monkeys (Macaca mulatta) using positron emission tomography (PET). For quantitative analysis of D1 receptors, [11C]SCH23390 was used and phosphodiesterase type-IV (PDE-IV) activity, as an index of cAMP system, was estimated by two scans with R- and S-[11C]rolipram. Significant age-related decreases in D1 receptor binding were observed in the striatum and frontal cortex. Analysis of uptake of R- and S-[11C]rolipram indicated age-related decreases in PDE-IV activity showing 22.0 and 25.2% decreases in the striatum and frontal cortex, respectively, while no significant changes were observed in the cerebellum. With systemic preadministration of the dopamine D1 receptor antagonist SCH23390 (0.2, 0.6, and 2 mg/kg), the PDE-IV activities in the striatum and frontal cortex were dose-dependently suppressed in both age groups. However, the degree of suppression by SCH23390 was more marked in young than in aged monkeys. These results demonstrate that the striatal cAMP second-messenger system activity as well as its functional response to dopamine D1 antagonist showed age-related impairment in the brain.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2002

Rat studies comparing 11C-FMAU, 18F-FLT, and 76Br-BFU as proliferation markers.

UNLABELLED: We analyzed and compared 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-[methyl-(11)C]thymine ((11)C-FMAU), 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT) and 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-[(76)Br]bromouracil ((76)Br-BFU) with respect to tissue uptake, DNA incorporation, and excretion modulation in rats. The goal of the investigation was to evaluate the efficiency of the 3 nucleoside tracers as potential tracers for measuring proliferation. METHODS: Sprague-Dawley rats were divided into 3 groups and administered 5 MBq (11)C-FMAU, 1 MBq (18)F-FLT, or 2 MBq (76)Br-BFU. For each tracer, a subgroup was also administered 6 mg/kg cimetidine. The rats in the (11)C-FMAU group were killed at 5, 20, 40, 60, and 80 min after injection; the rats in the (18)F-FLT group were killed at 80 min and 2 and 4 h; and the rats in the (76)Br-BFU group were killed at 5, 20, 40, and 80 min and 2, 4, 6, and 24 h. Samples of blood, liver, kidney, spleen, and intestine were taken, and the radioactivity was measured. DNA separation was made in the samples of spleen, and the radioactivity in the DNA fraction was measured. RESULTS: Maximal uptake of radioactivity was seen in the spleen and intestine, organs with active DNA synthesis. The highest relative radioactivity uptake was at 60 min in the (11)C-FMAU groups and at 4 h in the (18)F-FLT group. In the (76)Br-BFU group, the uptake increased gradually during the observation period, and uptake of radioactivity increased markedly in rats receiving cimetidine. Cimetidine did not affect radioactivity uptake in the (11)C-FMAU or (18)F-FLT groups. The fraction of radioactivity in DNA was 78% in spleen at 60 min in the (11)C-FMAU group, 80% at 60 min and 97% at 4 h in the (76)Br-BFU group. The DNA-incorporation was only 2% in the (18)F-FLT group. CONCLUSION: (76)Br-BFU predominantly incorporates into DNA and has great potential as a PET tracer for the assessment of proliferation in vivo. (11)C-FMAU also may have potential as a proliferation marker, but the observation time is limited. (18)F-FLT does not incorporate into DNA and is therefore not a direct marker of proliferation.

Animals↗