Altered immunoglobulin metabolism in systemic lupus erythematosus and heumatoid arthritis.

IgG and IgM metabolism was evaluated in 10 patients with systemic lupus erythematosus (SLE), 10 patients with rheumatoid arthritis (RA), and in seven normal volunteers. The biological half-lives of purified IgG and IgM, labeled with (131)I and (125)I, respectively, were determined by serial measurements of radioactivity in the blood and urine with a gamma well counter, and by serial counts of total body radioactivity in a total body counting chamber. The mean survival half-life for IgG in patients with SLE was 8.2 days as compared to an average of 18 days in normal controls. An average of 10.1% of total body IgG was catabolized daily compared to a mean of 3.9% in normal controls. Turnover of IgM in patients with SLE was, with very few exceptions, normal. In contrast, patients with rheumatoid arthritis revealed a milder abnormality of IgG metabolism, but markedly abnormal IgM catabolism with a mean half-life averaging 5.9 days as compared to 9.3 days in control subjects. An average of 14.2% of total body IgM was catabolized daily in patients with RA as compared to 8.1% in normal controls. Our data suggest that there are basic differences between patients with RA and SLE in the synthesis and catabolism of IgG and IgM not readily apparent from serum IgG and IgM concentration. Abnormal IgG and IgM metabolism may be related to underlying immunological mechanisms in these diseases. Immunoglobulin turnover studies appear to be an additional means for the characterization of rheumatic diseases.

The effect of azathioprine on gammaglobulin synthesis in man.

The effect of azathioprine therapy on gammaglobulin synthesis was evaluated in nine patients with rheumatic disorders. The rates of synthesis of IgG and IgM were calculated before and after 4 months of azathioprine treatment using turnover studies of radioiodinated gammaglobulins. The synthesis of IgG decreased 33.4% of the initial IgG synthetic rate. Seven of nine patients showed reductions of IgG synthesis ranging from 16.8 to 74.1%. IgM production decreased from 24.5 to 74.2% in eight of nine patients with a mean reduction of 40.9%. Studies before and after a control period of 4 months of placebo in six patients revealed a mean increase in IgG and IgM synthesis. Serum immunoglobulin concentrations after 4 months of azathioprine treatment were not consistently reduced and did not parallel changes in immunoglobulin synthesis. Reduced gammaglobulin synthesis may play a role in the therapeutic action of this and other "immunosuppressive" drugs.

A noninvasive positron computed tomography technique using oxygen-15--labeled water for the evaluation of neurobehavioral task batteries.

A technique is described that provides information about relative cerebral responses to differing neurobehavioral tasks in normal subjects studied with positron computed tomography and oxygen-15-labeled water. Simulation studies demonstrate that this technique is sensitive to changes in true local CBF within a physiological range and tends to underestimate relative flow changes at high flow values (greater than 30 ml min-1 100 g-1) and to overestimate these changes for flow values of less than 25 ml min-1 100 g-1. Image acquisition times of 60 s following the arrival of oxygen-15-labeled water in the brain were the most accurate for identifying such relative changes between radioisotope administrations and were not limited by statistical noise from total image counts. Studies in normal volunteers indicate that the technique is highly reproducible, demonstrating a coefficient of variation for small (less than 2 cm2) regions of 2.98 between studies in the same state. Visual stimulation studies in normal volunteers demonstrated relative radioisotope concentration changes between control and stimulated states that are in good agreement with similar results obtained using the same stimulation paradigm but with the use of fluorodeoxyglucose to determine cerebral glucose metabolism.

The C15O2 build-up technique to measure regional cerebral blood flow and volume of distribution of water.

A new method to measure regional CBF (rCBF) and volume of distribution of water is presented. It centres on recording the tissue build-up and retention of 15O-labelled water during the continuous inhalation of 15O-labelled carbon dioxide. Simultaneously, the arterial concentration is continuously monitored, and corrections for delay and dispersion in the recorded response are made by curve fitting. The values for the volume of distribution of water obtained in four normal subjects were close to reported in vitro values. Using the same fixed distribution volumes for both build-up and steady-state studies resulted in comparable rCBF values for both techniques.

13N-labeled L-amino acids for in vivo assessment of local myocardial metabolism.

The hot cell synthesis of sterile, pyrogen-free 13N-labeled L-amino acids was accomplished by employing the appropriate immobilized enzymes on a CNBr-activated Sepharose support and using remote, semiautomated systems. The syntheses were completed 6-12 min after cyclotron production of [13N]ammonia. Myocardial time-activity curves after intracoronary injection of 13N-labeled L-amino acids in dogs were triexponential in both normal and ischemic myocardium. Higher retention of 13N activity was observed in ischemic segments. Positron computed tomography imaging also showed increased uptake of 13N-labeled L-glutamate and L-alanine in ischemic segments compared with normal myocardium when blood flow corrections were made. Myocardial transaminases are primarily responsible for the observed retention fractions. It suggests the participation of the carbon skeletons of these amino acids in the Krebs cycle.

Imaging small pulmonary ischemic lesions after radioactive carbon monoxide inhalation.

A new method is described for imaging small ischemic regions in the lung immediately after a single breath of radioactive carbon monoxide (11CO). A tungsten-collimated scintillation camera is used to visualize the 0.51-MeV annihilation photons due to the 11C. In normal dogs the entire field is cleared of 11CO within 10 sec. However, in dogs with experimentally occluded 2-mm-diam segmental arteries, the ischemic but well-ventilated segment appears as a region of persistent high radioactivity, due most likely to temporary entrapment of 11CO-labeled red blood cells in the ischemic region. This technique also provides a simple noninvasive means for instantly labeling the systemic circulation without left heart catheterization.

Production by compact cyclotron of radiochemically pure iodine-123 as iodide for synthesis of radiodiagnostic agents.

Iodine-123-labeled radiopharmaceuticals are desirable because they give a high flux of 159-keV photons and a low radiation exposure per millicurie. Procedures suited to a compact cyclotron were developed to produce 50-mCi batches of radiochemically pure iodine-123 as iodide. Iodine-123 is separated from proton-irradiated tellurium-124 by distillation. Aqueous iodide is readily obtained by reduction with thiosulfate. Anhydrous iodide is extracted from the distillate iwth methyl ethyl ketone. The procedures for isolating radiochemically pure iodide are trouble-free, convenient, and reliable. Iodine-123-labeled o-iodohippurate and 16-iodo-9-hexadecenoic acid prepared from our iodide are now being used in clinical trials.

Collimation for imaging the myocardium.

Line-source response functions and modulation transfer functions (MTFs) were used to compare the resolution obtained with four myocardial-imaging agents: 129Cs, 43K, 13N-ammonia, and 81Rb contamination. When an Anger camera with pinhole collimator was used, the order of decreasing resolution was 129Cs, 43K, 13N, and 81Rb. Two techniques were employed to determine the extent to which spatial resolution could be improved. The first, involving the addition of lateral shielding, improved the MTFs for all the agents studied. The second, which utilized a subtraction mode, gave the best overall results. With the second method the MTF curves for 129Cs and 43K became very similar and were superior to both 81Rb and 13N. Both techniques were found useful in improving the spatial resolution of certain myocardial-imaging agents by reducing or eliminating the effects of penetration of the pinhole collimator walls by high-energy photons.

Experimental basis of myocardial imaging with 123I-labeled hexadecenoic acid.

Progress in myocardial perfusion imaging has been slowed by the lack or radiopharmaceuticals with suitable physical and biologic characteristics. Hexadecenoic acid, terminally labeled with 123I, partially overcomes these limitations by providing a compound that concentrates in the myocardium in proportion to relative regional blood flow and carries a gamma-emitter with desirable detection and imaging qualities. After intravenous injection in experimental animals, the clearance half-times of hexadecenoic acid for blood and myocardium are 1.7 and 20 min, respectively. These values compare favorably with 18-carbon fatty-acid analogs labeled with 11C. In acute and chronic infarction, similar distribution patterns are found for hexadecenoic acid and 43K, which indicates that hexadecenoic acid is a suitable substitute for the potassium analogs now in use for myocardial imaging. Because of the high count rates obtainable with 123I-hexadecenoic acid, good-guality images can be acquired in as little as 2-3 min per view. Iodine-123-hexadecenoic acid is potentially a useful radiopharmaceutical for clinical application.

The unit operations approach applied to the synthesis of [1(-11)C]2-deoxy-D-glucose for routine clinical applications.

An approach to the design of remote semiautomated chemical processing systems has been developed and tested in more than 750 production runs. This design stresses the idea of unit operations, which allows maximum flexibility while maintaining the highest possible standards regarding safety, reliability, efficiency, and practicality. Application of this approach has resulted in the development of a simple and reliable remote semiautomated synthesis system for the routine production of [1(-11)C]2-deoxy-D-glucose. Use of this system results in the preparation of a sterile, pyrogen-free product suitable for human injection after a synthesis time of 50 min, with radiochemical purity of greater than 98% and yields (25-30%) permitting quantitative measurements using positron computed tomography.

L-[1-11C]leucine: routine synthesis by enzymatic resolution.

L-[1-11C]leucine, suitable for the determination of cerebral protein synthesis rates in man using positron emission tomography, has been synthesized using a modified Bucherer-Strecker reaction sequence. The isolation of the pure L-amino acid isomer from the enantiomeric mixture, initially obtained using either an open or closed reaction vessel, was achieved using a D-amino acid oxidase/catalase enzyme complex immobilized on a Sepharose support. The O2 required by the D-amino acid oxidase as the hydrogen acceptor was supplied by catalase. The L-[1-11C]leucine was obtained with a radiochemical purity of greater than 99% and with a radiochemical yield of 25%. Using a remote, semiautomated synthesis system, typical production time was 30-40 min after preparation of H11CN. The use of immobilized enzymes for rapid and effective resolution of amino acid enantiomers eliminates the possibility of protein contamination and assures the production of a sterile, pyrogen-free product.

Positron ranges obtained from biomedically important positron-emitting radionuclides.

Positron ranges were obtained experimentally for several nuclides used in scintigraphic imaging. The nuclides examined were 13C, 13N, 15O, 18F, 68Ga, and 82Rb. The results are discussed with respect to the ultimate spatial resolution obrained in a scintigraphic image.

Evaluation of myocardial metabolism, with N-13- and C-11-labeled amino acids and positron computed tomography.

To evaluate the utility of labeled L-amino acids (AA) for imaging regional myocardial AA metabolism by positron computed tomography (PCT), the myocardial uptake and clearance of Ala,* Glu, Gln, Asp, Leu tagged with N-13, and of C-11-tagged Asp, and oxaloacetate (Oxal), were examined in 44 experiments at control, during ischemia, and after transaminase inhibition. The myocardial time-activity curves recorded after intracoronary tracer injection had two clearance phases (an early and a late) for all N-13 AA, and three (early, intermediate, late) for the two C-11 compounds, with significantly different clearance half-times of 18.7 +/- 8.0 (s.d.) sec for the early phase, 141.7 +/- 56.5 sec for the intermediate, and 61.2 +/- 43.5 min for the late phase. The residual fractions ranged from 0.07 to 0.23 in normal myocardium, and consistently increased with ischemia by 0.01-0.07 for N-13-labeled Ala, Glu, Asp, and Leu, but not for N-13 Gln and C-11 compounds. Transaminase inhibition shortened the half-times of the late phases of N-13-labeled Ala, Glu, Asp, and Leu; had no effect on t1/2 of N-13 Gln and C-11 Oxal; and resulted in a loss of C-11 CO2 production and of the intermediate phase for C-11 Asp. On the PCT images, N-13 activity from labeled Ala and Glu was not decreased in an ischemic segment despite a significant flow reduction, as demonstrated by N-13 NH3 imaging and labeled microspheres. From the results, a three-compartment tracer kinetic model is proposed for the noninvasive quantification of Krebscycle activity, protein synthesis, and metabolic derangements related to ischemia.

Remote, semiautomated production of F-18-labeled 2-deoxy-2-fluoro-D-glucose.

A routine production system for 2-deoxy-2-[18F]fluoro-D-glucose (2-18FDG) for medical use is presented. The method involves the preparation of F-18-labeled F2 by the 20Ne(d, alpha) 18F reaction, subsequent fluorination of 3,4,6-tri-o-acetyl-D-glucal, purification, and hydrolysis of the appropriate diastereoisomer to obtain 2-18FDG. These operations are performed using a completely remote, semiautomatic system. There have been no failures in more than 220 consecutive production runs. Currently, two preparations per day of 15-25 mCi of 2-18FDG are routinely performed, with a radiochemical purity, measured by TLC, in excess of 95% and with less than 1 mR radiation exposure to the chemist. Reaction conditions, operational variables, and systems are described in detail.

Synthesis and myocardial kinetics of N-13 and C-11 labeled branched-chain L-amino acids.

Glutamate dehydrogenase (GDH), immobilized on CNBr-activated Sepharose supports, was used with N-13 ammonia to aminate alpha-ketoisocaproic acid (KIC), and alpha-ketoisovaleric acid (KIV) to produce N-13-labeled branched-chain L-amino acids with radiochemical yields ranging from 29% to 35%. From kinetic and practical considerations, pH 7.5-8.0 was established to be optimal for the synthesis of N-13-labeled branched-chain-L-amino acids. Myocardial time-activity curves in dogs at control, during low-flow ischemia, reperfusion, and after transaminase inhibition following intracoronary bolus injection of the N-13-labeled amino acids were biexponential. Higher retention of N-13 activity was observed in ischemic segments both during low-flow ischemia (29.2%) and reperfusion (23.2%) when compared with controls (20.0%), (n = 4). On the other hand, transaminase inhibition decreased residue fractions from 21.0% at control to 13.9% (n = 4). The residual activity with L-[1-11C]leucine allows for the calculation of protein synthesis rates.