Biomedical subjects

N Satyamurthy

Publications and source records attributed to N Satyamurthy.

At least 55 records · Page 3Linked to original sources

PubMed1992

Evaluation of the skeletal kinetics of fluorine-18-fluoride ion with PET.

To evaluate the feasibility of quantitatively assessing regional skeletal fluoride uptake in humans in focal and generalized bone disease, we investigated the skeletal kinetics of [18F]fluoride ion with dynamic PET imaging. Dynamic image sets were acquired over a 60-min interval in a multiplane PET device, and input functions (plasma 18F time-activity curves) were measured directly from arterialized blood and, in some cases, determined from image-derived left ventricular cavity activity measurements. Our results indicate: 1. A steady-state ratio of [18F]fluoride ion concentration in plasma to whole blood greater than unity (1.23 for plasma to directly assayed whole blood and 1.44 for plasma to left ventricular cavity imaged concentrations. This concentration difference produces a scaling factor that must be considered when using image derived or directly measured input functions. 2. The preferred tracer kinetic model configuration for [18F]fluoride ion skeletal kinetics is a three compartment model that includes a "bound" and "unbound" bone [18F]fluoride ion compartment. 3. The rate constant for forward transport of [18F]fluoride ion from plasma to the extravascular space of bone (K1) and the regional blood volume parameter generate estimates of bone blood flow and vascular volume, respectively, that are in the physiologic range of reported for mammals. Estimates of the uptake constant for fluoride in bone, using nonlinear regression (KNLR = 0.0360 +/- 0.0064 ml/min/ml), are in very good agreement with an estimate of the same parameter obtained with Patlak graphical analysis (KPAT = 0.0355 +/- 0.0061 ml/min/ml). 4. Generating parametric images of KPAT facilitates quantification of regional bone [18F]fluoride ion kinetics. The method is computationally practical, and, with either the parametric imaging approach or with standard region of interest analysis, can be used to generate quantitative estimates of fluoride uptake (a "bone metabolic index") in focal skeletal regions or in more generalized distributions.

Adult↗

PubMed1991

L-6-[18F]fluoro-dopa metabolism in monkeys and humans: biochemical parameters for the formulation of tracer kinetic models with positron emission tomography.

Characterization of peripheral and cerebral L-3,4-dihydroxy-6-[18F]fluorophenylalanine (FDOPA) metabolism in humans and monkeys has shown FDOPA to be an analogue of L-DOPA for the study of the dopaminergic system with positron emission tomography (PET). In human studies with carbidopa pretreatment, L-3,4-dihydroxy-6-[18F]fluoro-3-O-methylphenylalanine (3-OMFD) was the only FDOPA metabolite detected in plasma. FDOPA administration in monkeys resulted in selective accumulation of FDOPA metabolites in central dopaminergic regions, whereas 3-OMFD of peripheral origin was uniformly distributed among putamen, caudate, frontal cortex, and cerebellum. At 60 min, 3-OMFD and 6-[18F]fluorodopamine (FDA) each represented approximately 35% of the total activity, the remainder being FDOPA and FDA metabolites. These data on monkey and human FDOPA metabolism provide the basis for the configuration of an FDOPA tracer kinetic model with PET.

Adult↗

PubMed1991

Kinetics and modeling of L-6-[18F]fluoro-dopa in human positron emission tomographic studies.

Kinetics of L-3,4-dihydroxy-6-[18F]fluorophenylalanine (FDOPA) in striatum and cerebellum were measured in 10 normal human subjects with positron emission tomography (PET) from 0 to 120 min after an intravenous bolus injection of the tracer. The time course of the arterial plasma concentrations of the tracer and its metabolites was also assayed biochemically. FDOPA compartmental models that are based on biochemical information were investigated for their consistency with the measured striatal and cerebellar tissue kinetics. A modeling approach was also developed for separating plasma FDOPA and metabolite time-activity curves from the measured total 18F time-activity curve in plasma. Results showed that a model consisting of three separate compartments for tissue FDOPA, tissue 6-[18F]fluorodopamine (FDA) and its metabolites, and tissue L-3,4-dihydroxy-6-[18F]fluoro-3-O-methylphenylalanine (3-OMFD) could describe adequately the striatal kinetics in humans. Based on this model, the FDOPA transport constant across the blood-brain barrier (BBB) (K1), the FDOPA decarboxylation rate constant (k3), and the turn-over rate constant of FDA and its metabolites (k4) could be estimated by model fitting to the tissue kinetics and were found for the normal subjects to be 0.031 +/- 0.006 ml/min/g (mean +/- SD), 0.041 +/- 0.015/min, and 0.004 +/- 0.002/min, respectively. About 50% of the FDOPA that crossed the BBB from plasma to striatum was decarboxylated. The decarboxylation constant with respect to plasma FDOPA (K3) was 0.015 +/- 0.003 ml/min/g. The BBB transport corresponded to a permeability-surface area product of 0.032 ml/min/g for FDOPA. For 3-OMFD, the BBB transport was 1.7 times faster. The effects of tissue heterogeneity on the FDOPA kinetics and on the estimated model parameters were also investigated. The usefulness and implications of these findings for interpretation of PET FDOPA studies are discussed.

Adult↗

PubMed1991

Modelling approach for separating blood time-activity curves in positron emission tomographic studies.

A modelling approach is developed to generate the full time course of an injected radiotracer and its labelled metabolites in plasma/blood, based on measurements of the total radioactivities in withdrawn plasma/blood samples. A compartmental model is used to describe the conversion of an injected tracer to its metabolites in the body. The model equation is formulated with the total radioactivity concentration curve as the input function. The utility and characteristics of the approach in quantitative positron emission tomographic (PET) studies are shown with two examples. In the first example, using the tracer 6-[18F]fluoro-L-dopa (FDOPA), the approach is shown to derive the full time course of plasma FDOPA and its metabolites. In the second example of dynamic 15O oxygen PET, the approach is used to solve a deconvolution problem to give separated time-activity curves of 15O oxygen and 15O water in blood. The modelling approach improves the separation of blood/plasma time-activity curves and leads to better quantitative interpretation of PET results.

Dihydroxyphenylalanine↗

PubMed1991

Assessment of 18F gaseous releases during the production of 18F-fluorodeoxyglucose.

Fluorodeoxyglucose labeled with 18F (18F-FDG) is the most commonly used radiopharmaceutical in positron emission tomography (PET). Fluorine-18-labeled FDG is used as a diagnostic tool in PET studies to monitor the physiology of the brain, diagnose heart function and disease, and to image cancerous tumors. At the University of California, Los Angeles (UCLA), three cyclotrons produce [18F]-fluoride ion using 18O-enriched water targets. Fluorine-18, which has a half-life of 109.8 min, is produced using an 18O(p.n.)18F reaction and is chemically processed to yield 18F-FDG. This study presents data which demonstrate that during the radiochemical processes involved in the production of 18F-FDG, gaseous effluent containing 18F is released. Forty cyclotron production runs with average end of cyclotron bombardment activities of 15.9 +/- 1.88 GBq (430 +/- 50.8 mCi) and end of radiochemical synthesis activities of 5.40 +/- 1.27 GBq (146 +/- 34.3 mCi) yield 18F gaseous effluent releases ranging from 0 to 2560 MBq (0 to 69.2 mCi) with a mean of 437 MBq (11.8 mCi). Temporal correlation of the 18F gaseous releases during 18F-FDG radiochemical production has tied the 18F release to the addition of the glucose precursor (mannotriflate) and ethyl ether in the radiochemical processing. The results are presented in terms of activities released and dilution factors required from the release stack point to maintain controlled (occupational) and uncontrolled (public) area limits in accordance with the recommendations of the International Commission on Radiological Protection and the regulatory requirements of the federal government.

Air Pollutants, Radioactive↗

PubMed1990

6-[18F]fluoro-L-dopa probes dopamine turnover rates in central dopaminergic structures.

6-[18F]Fluoro-L-DOPA (FDOPA) cerebral kinetics and metabolism were correlated in normal primates (Macaca nemestrina) and primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced unilateral Parkinsonism. Application of a tracer kinetic model to positron emission tomography (PET) data indicated that the model allows reliable estimation of FDOPA blood brain barrier transport, decarboxylation and release of stored 6-[18F]fluorodopamine (FDA) radioactivity in normal striatum (k4 = 0.005/min, turnover half-time greater than or equal to 2 hr), in agreement with biochemical data. PET scans of MPTP treated monkeys revealed 40-50% reduction in total striatal activity in comparison with pre-MPTP scans. Monkey brain biochemical analysis revealed that the reduction in activity was mainly due to a decrease in FDA and its metabolites, 6[18F]fluorohomovanillic (FHVA) and 6-[18F]fluoro-3, 4-dihydroxyphenylacetic acid (FDOPAC). The remaining activity in tissue was 3-0-methyl-6-[18F]fluoro-L-DOPA (3-OMFD) of peripheral origin. The (FHVA + FDOPAC)/FDA ratio was 1:2 in normal putamen and greater than or equal to 6:1 in the lesioned putamen, indicative of a dramatic increase in turnover of FDA. Both kinetic and biochemical data indicate that FDOPA labels a slow turnover rate pool of dopamine in rat and primate brain. This turnover rate for stored dopamine (DA) is accelerated with dopaminergic cell losses (e.g., MPTP-induced Parkinsonism).

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1990

N-[18F]fluoro-N-alkylsulfonamides: novel reagents for mild and regioselective radiofluorination.

N-[18F]fluoro-N-alkylsulfonamides were synthesized by the fluorination of secondary sulfonamides with [18F]F2. Radiochemical yields up to 45% (out of a maximum possible yield of 50%) for these reactions have been realized. The N-[18F]fluorosulfonamides rapidly and regiospecifically fluorinate a variety of Grignard reagents and aryllithium under very mild conditions to give 18F-labeled derivatives in good yields.

Fluorine↗

PubMed1990

Synthesis of 4-[18F]fluoro-L-m-tyrosine: a model analog for the in vivo assessment of central dopaminergic function.

4-[18F]Fluoro-L-m-tyrosine (6), a new analog of L-dopa for probing the presynaptic dopaminergic system by positron emission tomography has been synthesized in good radiochemical yields via the regioselective fluorodemercuration of the 4-mercurio derivatives 4a and 4b with 18F-labeled acetylhypofluorite. The chemical, radiochemical and enantiomeric purities were determined to be greater than 99%. The key step in the synthesis of the precursors 4 was the mercuration of the protected L-m-tyrosine 3. The position of mercuration on the aromatic ring was gleaned from the 13C-NMR spectral data. The non-radiolabeled counterpart of 6 was also synthesized. Structural analyses of all these compounds were carried out by 1H-, 13C-, 19F-NMR and mass spectroscopy.

Fluorine Radioisotopes↗

PubMed1990

3-(2'-[18F]fluoroethyl)spiperone, a potent dopamine antagonist: synthesis, structural analysis and in-vivo utilization in humans.

The synthesis of 3-(2'-[18F]fluoroethyl)spiperone (1c), a radiotracer useful for imaging the brain dopamine receptor system in vivo using positron emission tomography, is described. Precursors of 1c, the functional 3-N-alkyl derivatives of spiperone (4), were prepared by the alkylation of the amide group in spiperone (2a) by 1,2-disubstituted ethanes under phase transfer conditions. A comprehensive evaluation of the reaction of the derivatives 4a-h with no-carrier-added K18F/Kryptofix clearly indicated that the ketalized derivatives 4e-h were the choice of the precursors for 1c. The i.r., MS and NMR spectral data suggested that under phase transfer reaction conditions, the amide nitrogen was preferentially alkylated. To provide a firm basis for comparison with related analogues, an x-ray analysis was performed on a single crystal of 3-(2'-fluoroethyl)spiperone (1d). The tomographic behavior of 1c in human brain tissue was measured for more than 7 h and was consistent with the labeling of dopamine D-2 receptors.

Brain↗

PubMed1990

Remote, semiautomated production of 6-[18F]fluoro-L-dopa for human studies with PET.

Regioselective radiofluorodemercuration of the 6-mercurio derivative 5 with [18F]acetylhypofluorite afforded, after acidic hydrolysis, 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine (6-FD, 1) with a radiochemical yield of 11% (decay corrected and based on the total amount of [18F]F2 recovered from the target). 6-FD was obtained with a chemical and radiochemical purity of greater than 99% and with a level of mercury in the final preparation of less than 20 ppb. Utilization of a remote, semiautomated production system, resulted in the preparation of a sterile, pyrogen-free product suitable for human injection after a synthesis time of 50 min.

Dihydroxyphenylalanine↗

PubMed1989

Computer-controlled radiochemical synthesis: a chemistry process control unit for the automated production of radiochemicals.

A computer-controlled general purpose chemistry process control unit (CPCU) suitable for the automated production of radiochemicals has been developed. This valve-and-tubing synthesis system can be user programmed to accommodate a variety of chemical processes. In a practical demonstration of its utility, the CPCU has been configured and programmed to synthesize 2-deoxy-2-[18F]fluoro-D-glucose (2-[18F]FDG) using aqueous [18F]fluoride ion. Using this instrument, the yield of 2-[18F]FDG from [18F]fluoride ion is 54.9% (+/- 11.2%, n = 125) corrected to EOB, after a synthesis time of 50-55 min. The average total activity produced (for runs of 5-10 microA) is 28.1 mCi/microA (+/- 5.03 mCi/microA). Thus, the amount of 2-[18F]FDG produced from a 10 microA for 1 h bombardment was 154.3 mCi (+/- 27.4 mCi). The unit has been similarly configured and programmed to synthesize 2-deoxy-2-[18F]fluoro-D-mannose (48% EOB), 3-(2'-[18F]fluoroethyl)spiperone (29% EOB), and [18F]fluoroacetate (66% EOB) from aqueous [18F]-fluoride ion, and 2-[18F]FDG from gaseous acetyl hypo[18F]fluorite (20% EOB).

Computers↗

PubMed1989

3-(2'-[18F]fluoroethyl)spiperone: in vivo biochemical and kinetic characterization in rodents, nonhuman primates, and humans.

3-(2'-[18F]fluoroethyl)spiperone (FESP), a recently developed dopamine D2-receptor binding radiopharmaceutical, was used for dynamic characterization of dopamine-receptor binding in Macaca nemestrina monkeys and humans with positron emission tomography (PET). FESP in vitro binding properties to the dopamine receptor (IC50 = 1.5 nM) are similar to those of spiperone. Serial PET scans in monkeys after intravenous bolus injection of FESP revealed specific radioactivity accumulation in striatum (rich in dopamine D2-receptors), whereas radioactivity concentration declined after 20 min in frontal cortex (serotonin receptors) and more rapidly in cerebellum (nonspecific binding). Specific dopamine D2-receptor binding was saturated with increasing concentrations of radioligand (specific activity range: 1-10,000 Ci/mmol), was stereospecifically blocked with (+)butaclamol (0.5 mg/kg), and showed only partial displacement with spiperone (200 micrograms/kg, i.v. administration 90 min after FESP injection). From PET experiments with FESP in humans, it is possible to visualize accumulation of radioactivity in striatum in a manner similar to that observed in monkeys and, ex vivo, in rodents (adult male Sprague-Dawley rats). Biochemical analyses in rat brain revealed that the activity (approximately 90%) in striatum was unmodified FESP up to 4 h after injection. On the other hand, FESP was metabolized peripherally (rat greater than monkey greater than human), with only 11% of plasma radioactivity remaining as intact FESP in rodents and 54% in humans after 2 h. Based on these interspecies scaling pharmacokinetic data, it is unequivocal that FESP peripheral metabolites do not significantly contribute to the accumulated radioactivity in striatal tissue. Therefore, it is concluded that FESP is suitable for the quantitative estimation of dopamine D2-receptor sites using PET.

Animals↗

PubMed1989

Models for in vivo kinetic interactions of dopamine D2-neuroreceptors and 3-(2'-[18F]fluoroethyl)spiperone examined with positron emission tomography.

The in vivo tracer kinetics of 3-(2'-[18F]fluoroethyl)spiperone (FESP) in the caudate/striatum and cerebellar regions of the human and monkey brain were studied with positron emission tomography (PET). The minimal model configuration that can describe the kinetics was determined statistically. Three two-compartment model configurations were found to be suitable for describing the kinetics in caudate/striatum and cerebellum: (1) a nonlinear model (five parameters) applicable to studies using nontracer (partially saturating) quantities of FESP in monkey striatum, (2) a linear four-parameter model applicable to the caudate/striatal and cerebellar kinetics in human and monkey studies with tracer quantities of FESP, and (3) a linear three-parameter model derived from the four-parameter model by assuming irreversible binding applicable to tracer studies of the human caudate. In the human studies, when the caudate kinetics (n = 4) were fit by model 2 (with four parameters), the value of the in vivo ligand dissociation constant kd was found to be 0.0015 +/- 0.0032/min. The three-parameter model (model 3) was found to fit the data equally well: this model is equivalent to model 2 with kd set to zero. In the monkey studies, it was found that for short (90 min) studies using tracer quantities of FESP, model 2 fit the striatal kinetics better than model 3. The parameters estimated using model 2 (four parameters) were in better agreement with those estimated by the nonlinear model (model 1) than those estimated using model 3 (three parameters). The use of a graphical approach gives estimates of the plasma-tissue fractional transport rate constant K1 and the net uptake constant K3 comparable to estimates using model 3 for both human and monkey studies.

Adult↗

PubMed1989

A double-injection technique for in vivo measurement of dopamine D2-receptor density in monkeys with 3-(2'-[18F]fluoroethyl)spiperone and dynamic positron emission tomography.

Dopamine D2-receptor density in striatum of monkey was measured with 3-(2'-[18F]fluoroethyl)spiperone (FESP) and dynamic positron emission tomography (PET), using a double-injection technique. A first bolus of high specific activity (SA) FESP (5 mCi; approximately equal to 1 Ci/mumol) was injected i.v.; 90 min later, a second bolus of lower SA FESP (5 mCi; approximately equal to 0.04 Ci/mumol) was injected. A dynamic PET study was performed to measure the kinetics of FESP in striatum over 180 min, and the metabolite-corrected concentration of FESP in plasma as a function of time was obtained from arterial blood samples. A nonlinear compartmental model that took into account the saturability of the receptor binding was used to describe the kinetics of FESP in striatum. Model parameters were estimated by regression with a constraint based on information about the equilibrium dissociation constant of the ligand-receptor binding. Dopamine D2-receptor density in striatum was estimated to be 25.9 +/- 12.7 pmol/g in seven Macaca nemestrina monkeys. The method does not require the use of cerebellum as a reference tissue region and an estimate of dopamine D2-receptor density can be obtained from a single study.

Animals↗

PubMed1986

Stereospecific approach to the synthesis of [18F]2-deoxy-2-fluoro-D-mannose.

The reaction of methyl 4,6-O-benzylidene-3-O-benzyl-2-O-trifluoromethanesulfonyl-beta-D- glucopyranoside in acetonitrile at 75 degrees C for 30 min with [18F]tetra-n-butylammonium fluoride, followed by silica gel column chromatographic purification, gave the corresponding [18F]methyl 4,6-O-benzylidene-3-O-benzyl-2-fluoro-beta-D-mannopyranoside with complete regio- and stereoselectivity (42% radiochemical yield). Hydrolysis of the radiolabeled fluoromannopyranoside intermediate with either 6 N HCl or 50% methanesulfonic acid for 30 min at 120 degrees C, followed by purification by column chromatography (ion retardation resin and neutral alumina), gave pure [18F]2-deoxy-2-fluoro-D-mannose ([18F]2-FDM) with an overall radiochemical yield (from [18F]fluoride ion) of 34%. Extension of this methodology to the no carrier added (nca) synthesis under phase transfer conditions (Kryptofix 222/K 18F/acetonitrile) gave nca [18F]2-FDM in a radiochemical yield of 75%. Purity and identity of the fluorinated products were confirmed by 1H and 19F NMR spectroscopy. The synthetic procedure described here permits for the first time the routine preparation of large amounts of [18F]2-FDM for tomographic studies.

Fluorine↗

PubMed1986

No-carrier-added 3-(2'-[18F]fluoroethyl)spiperone, a new dopamine receptor-binding tracer for positron emission tomography.

No-carrier-added (NCA)3-(2'-[18F]fluoroethyl)spiperone (5), a new dopamine receptor-binding radiopharmaceutical for positron emission tomography, was synthesized by two different methods. Alkylation of the amide nitrogen in spiperone by NCA [18F]fluorobromoethane in the presence of a strong base gave 5 (Method A). Experimental methods were also developed for the syntheses of functional 3-N-alkylderivatives of spiperone such as 3-(2'-bromoethyl)- or 3-(2'-methylsulfonyloxyethyl)spiperone (4a and 4b, respectively). These derivatives (4) reacted with NCA Ag18F, Cs18F or K18F/Kryptofix 222 in acetonitrile or DMSO to give 5 (Method B). Method B, using K18F/Kryptofix 222 in acetonitrile provided 5 in multimillicure amounts (30-40% isolated radiochemical yield) with a specific activity of 2-10/mumol (EOS) in less than 60 min. This one-step, one-pot synthesis is simple, and the high radiochemical yield of 5, as well as the 110 min half-life of 18F, permit multiple tomographic studies a day with one preparation. Tomographic results in monkey brain with 5 are consistent with the labeling of dopamine-D2 receptor systems.

Animals↗

PubMed1984

The synthesis of 2-[F-18]fluoro-2-deoxy-D-glucose using glycals: a reexamination.

The reaction of [F-18]F2 with D-glucal in water proceeds sufficiently mildly at room temperature to present marked regiospecificity. After hydrolysis, analysis by Fourier-transform 19F-NMR showed the product to consist of a mixture of 2-fluoro-2-deoxy-D-glucose (2-FDG) and 2-fluoro-2-deoxy-D-mannose (2-FDM) in a 2:1 ratio, respectively. The presence of the mannose isomer has been revealed by extension of the 19F-NMR analyses to other literature methods for 2-FDG synthesis involving the electrophilic fluorinating agent acetyl hypofluorite. Reaction of acetyl [F-18] hypofluorite, prepared by the reaction of [F-18]F2 with solid sodium acetate trihydrate, with the appropriate glycal/solvent combination, followed by hydrolysis, has led to production of [F-18]2-FDG with a radiochemical purity of 95%.

Deoxy Sugars↗

PubMedDate not supplied

Imaging transgene expression with radionuclide imaging technologies.

A variety of imaging technologies are being investigated as tools for studying gene expression in living subjects. Noninvasive, repetitive and quantitative imaging of gene expression will help both to facilitate human gene therapy trials and to allow for the study of animal models of molecular and cellular therapy. Radionuclide approaches using single photon emission computed tomography (SPECT) and positron emission tomography (PET) are the most mature of the current imaging technologies and offer many advantages for imaging gene expression compared to optical and magnetic resonance imaging (MRI)-based approaches. These advantages include relatively high sensitivity, full quantitative capability (for PET), and the ability to extend small animal assays directly into clinical human applications. We describe a PET scanner (microPET) designed specifically for studies of small animals. We review "marker/reporter gene" imaging approaches using the herpes simplex type 1 virus thymidine kinase (HSV1-tk) and the dopamine type 2 receptor (D2R) genes. We describe and contrast several radiolabeled probes that can be used with the HSV1-tk reporter gene both for SPECT and for PET imaging. We also describe the advantages/disadvantages of each of the assays developed and discuss future animal and human applications.

Animals↗