Development of a reliable Hg-195m--Au-195m generator for the production of Au-195m, a short-lived nuclide for vascular imaging.

A new mercury-195m (T1/2: 41 hr) leads to gold-195m (T1/2: 30.6 sec) generator suitable for first-pass as well as steady-state radionuclide angiography studies has been developed. The distribution coefficients, Kd, for mercury (Hg-195m) and gold (Au-196), experimentally evaluated on chelating resin Chelex 100, showed this resin to be suitable as the column packing. Mercury-195m in a Trisma buffer solution at pH 7.40 was loaded on a chelating resin Chelex 100 column, together with gold carrier. Au-195m was eluted with an aqueous solution of 5% glucose in a 0.01M Trisma buffer at pH 7.70 (25 degrees C). Chemical assessment of the eluate has ensured that the eluted carrier-free gold is by no means colloidal: 80% is found in an ionic form, 20% as an uncharged species. Safe clinical use for routine diagnosis in humans is possible.

Radiation dosimetry for bolus administration of oxygen-15-water.

UNLABELLED: We describe the development of a biokinetic model which permits an estimation of organ activities and the dosimetry of a bolus of 15O-water. The aim of this study was to estimate time-activity functions and deduce the cumulated activities in different organs so that the radiation absorbed dose values can be estimated. METHODS: The model we used includes the right heart chambers, lungs, left heart chamber, brain, liver, kidneys, muscles, gastrointestinal tract and the remainder of the body. Activity in an organ will decay by physical decay with the decay constant, lambda, and can diffuse in the organ. An exception is the heart, where blood is ejected from the heart chambers. Depending on the location of the organ in relation to the blood sampling point, organ activities can be calculated by convolution or deconvolution. RESULTS: The radiation absorbed dose values were estimated and an effective dose equivalent HE of 1.16 microSv/MBq (4.32 mrem/mCi) as well as an effective dose E of 1.15 microSv/MBq (4.25 mrem/mCi) were calculated. The cumulated activities in select organs measured by PET gave good agreement with the values calculated by this model. CONCLUSION: The values of effective dose equivalent and effective dose for bolus administration of 15O-water calculated from the absorbed doses estimated by the proposed kinetic model are almost three times higher than those previously published. A total of 8700 MBq (235 mCi) of 15O-water can be administered if an effective dose of 10 mSv (1 rem) is accepted.

A new osmium-191/iridium-191m radionuclide generator system using activated carbon.

A new osmium-191/iridium-191m (191Os/191mIr) radionuclide generator system has been developed based on the absorption of K2OsCl6 (Os-IV) on 140-230 mesh heat-treated activated carbon. The generator is eluted with pH 2 saline solution containing 0.25 g/l Kl to give 191mIr in good yield. The generator eluent is neutralized to physiologic pH and isotonicity with Tris buffer immediately prior to i.v. injection. No scavenger column is required. As an example, elution of the prototype generator with a 2-ml bolus results in elution of 191mIr in approximately 18% yield with an 191Os breakthrough of only 2 X 10(-4)%/bolus. The prototype generator has consistent performance over a 2-wk period with no change in 191mIr yield or 191Os breakthrough. Loading of up to 1.5 Ci of 191Os results in no observed radiolysis. Continuous elution of this system is also possible with a mean 191mIr yield of 3.7%/ml and a mean 191Os breakthrough of 2 X 10(-5)%/ml at a flow rate of 12 ml/min. This new system represents a readily available source of 191mIr for radioangiography. Adsorbed radiation dose calculations indicate a total-body dose of only 3.9 mrad for a 100 mCi injected bolus.

Myocardial kinetics of potassium-38 in humans and comparison with copper-62-PTSM.

UNLABELLED: The aim of this study was to define the kinetics of 38K and its suitability to evaluate myocardial blood flow at rest and during pharmacological vasodilation in normal subjects. Potassium-38's kinetic characteristics were also compared to those of a 62Cu-pyruvaldehyde bis(n4-methyl-thio-semicarbazone) copper (II) (PTSM) flow tracer. METHODS: Potassium-38 and 62Cu-PTSM were injected at rest and after pharmacological vasodilation in six healthy volunteers. Dynamic PET acquisition was performed over 20 min and myocardial tracer retention calculated. Homogeneity of regional myocardial tracer distribution was also evaluated. RESULTS: High image quality of the heart was observed at rest and after dipyridamole with both tracers. Potassium-38 demonstrated prolonged myocardial retention with minimal lung and liver accumulation. In contrast to 38K, 62Cu-PTSM demonstrated high liver uptake which may hinder observation of the inferior wall of the myocardium. Copper-62-PTSM dipyridamole-to-rest retention ratio was 1.49. CONCLUSIONS: Potassium-38 and 62Cu-PTSM display suitable kinetics for the qualitative evaluation of blood flow and flow reserve in the human heart. Compared to 62Cu-PTSM, potassium-38, which does not show high liver uptake, may more accurately estimate blood flow in the inferior wall of the heart. However, accurate quantification of myocardial blood flow using 38K or 62Cu-PTSM retention appears to be limited to decreasing retention fraction at hyperhemic states.

Clinical usefulness of ultrashort-lived iridium-191m from a carbon-based generator system for the evaluation of the left ventricular function.

Ultrashort-lived 191mIr (4.96 sec; 63-74 and 129 keV photons) is potentially advantageous for first-pass radionuclide angiocardiography, offering the opportunity to perform repeat studies with very low absorbed radiation dose to the patient. Left ventricular (LV) first-pass studies were performed in 72 patients with 191mIr from a new bedside 1.3 Ci (48.1 GBq) 191Os/191mIr generator system using an activated carbon support that offers high 191mIr yields (15-18%) and consistent low 191Os breakthrough (2-4 x 10(-4)%/bolus). Using a single crystal digital gamma camera, uncorrected end-diastolic counts in the left ventricular representative cycle ranged from 10 up to 30 k counts. The reproducibility of repeated LV ejection fraction (LVEF) determination at 2-min intervals in 50 patients was r = 0.97, mean diff. = 2.08 +/- 1.55 EF units. Comparison between 191mIr (80-120 mCi; 2,960-4,400 MBq) and 99mTc (20-25 mCi; 750-925 MBq) LV count rates indicates a 3 wk useful shelf life of this new generator system for cardiac studies. Iridium-191m determined LVEF correlated closely with 99mTc determined LVEF in 32 patients (r = 0.96, mean diff. = 1.87 +/- 1.23 EF units). Parametric images for LV wall motion analysis were comparable with both isotopes. We conclude that rapid, repeat, and reproducible high count rate first-pass left ventricular studies can be obtained with 191mIr from this new 191Os/191mIr generator system using a single crystal digital gamma camera.

High-yield radiosynthesis and preliminary in vivo evaluation of p-[18F]MPPF, a fluoro analog of WAY-100635.

No-carrier-added 4-[18F]fluoro-N-[2-[1-(2-methoxyphenyl)-1 piperazinyl]ethyl-N-2-pyridinyl-benzamide (p-[18F]MPPF) was synthesized by nucleophilic substitution of the corresponding nitro compound in the presence of Kryptofix 222 and K2CO3 by microwave heating (3 min, 500 W) using a remotely controlled radiosynthesis. Baseline separation of p-[18F]MPPF from the nitro derivative was performed on a semipreparative HPLC C18 column. After Sep-Pak formulation, the radiopharmaceutical was obtained with a radiochemical yield of 25% (EOS) in about 70 min. Specific radioactivity averaged between 1-5 Ci/micromol EOS. Labelling of the ortho and meta derivatives was also attempted. Brain uptake of p-[18F]MPPF was studied with PET on fluothane-anesthetized cats. Following intravenous injection of p-[18F]MPPF, high accumulation of radioactivity was observed in the hippocampus and cerebral cortex. Low levels of radioactivity were observed in cerebellum. At 30 min, the mean hippocampus/cerebellum and cortex/cerebellum ratios were 5 and 3.8, respectively. The accumulation of the tracer was blocked by prior administration of reference WAY-100635, demonstrating the specificity of the ligand.

[(18)F]p-MPPF: aA radiolabeled antagonist for the study of 5-HT(1A) receptors with PET.

This paper summarizes the present status of the researches conducted with [(18)F]4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-fluorobenzamido ]ethyl]-piperazine known as [(18)F]p-MPPF, a new 5-HT(1A) antagonist for the study of the serotonergic neurotransmission with positron emission tomography (PET). This includes chemistry, radiochemistry, animal data (rats, cats, and monkeys) with autoradiography and PET, human data with PET, toxicity, and metabolism.

Performance of a single crystal digital gamma camera for first pass cardiac studies.

First pass radionuclide angiocardiography (FPRNA) has gained increasing interest because of the development of new 99Tcm-labelled perfusion agents and of new 191Os/191Irm generator systems. The aim of the study was to evaluate the performance capacities of a small field of view single crystal digital gamma camera for 99Tcm and 191Irm at high count rates. The camera dead time for 99Tcm (window 30%) was well corrected up to 300 kcps in fast acquisition mode using the relative decrease of a small shielded reference source. Using the decaying activity method for 191Irm the non-linearity response of the gamma camera was corrected by an 191Os reference soruce up to 210 kcps at 70 keV, 75 kcps at 129 keV and 320 kcps including both peaks. Saturation count rates were respectively 270 kcps, 150 kcps and 420 kcps and high count rate resolution (FWHM) 9.0, 7.3 and 10.3 mm. Since the accuracy of first pass measurements is more sensitive to count rate than to spatial resolution the 50-150 keV window was chosen for clinical studies. In data obtained from 32 ECG gated FPRNA patient studies, the whole field of view count rate during the left ventricular phase ranged from 100 to 250 kcps with 80 to 120 mCi (2960-4400 MBq) of 191Irm and 100 to 180 kcps with 20 to 25 mCi (750-925 MBq) of 99Tcm red blood cells permitting for both tracers accurate non-linearity correction.

Comparison between exercise myocardial perfusion and wall motion using 201Tl and 191Irm simultaneously.

By exploiting the ultrashort half-life 191Irm as tracer for left ventricular first-pass angiocardiography and 201Tl as myocardial perfusion agent, direct comparison between myocardial perfusion and regional wall motion was obtained during the same exercise stress test in patients with non-significant coronary artery disease, in patients with recent myocardial infarction, and in patients six weeks after successful percutaneous transluminal coronary angioplasty (PTCA). A good agreement between regional myocardial perfusion and regional wall motion was observed in patients with non-significant coronary artery disease and in most patients with recent myocardial infarction. In contrast, discrepancies occurred at maximal exercise in patients studied six weeks after successful PTCA: only 38% of the patients with no evidence of restenosis and with a completely normal myocardial perfusion scintigraphy had a normal regional wall motion at maximal exercise stress. According to these results, a normal uptake of 201Tl six weeks after PTCA would mean that the circulation has been successfully reestablished but without predicting the functional capacities of the myocardial cells which remain altered at least six weeks after the revascularization procedure in about two-thirds of the patients. We conclude that 191Irm in combination with 201Tl offers the opportunity of performing myocardial perfusion and wall motion studies simultaneously both at rest and during exercise.

[Effect of cortisone acetate on acid secretion induced by histamine, pentagastrin, gastrin and food in dogs]. / Effets de l' acétate de cortisone sur la sécétion acide provoquée par l' histamine, la pentagastrine, la gastrine et le repas chez le chien

The effects of long term treatment with cortisone on the gastric secretion induced by histamine, pentagastrin, porcine gastrin and a meal have been investigated in four dogs with both gastric fistula and Heidenhain pouch. Cortisone increased the postcibal acid output and the observed maximal acid response from the pouch to all three exogenous stimuli. The ED 50'S remained unchanged. The same effects although less marked were observed in the innervated stomach. These data indicate that the increased acid secretion observed after long term treatment with cortisone is largely due to an increased secretory capacity of the gastric mucosa. This latter could result from an increase in the number of secretory units or to partial removal of a non competitive inhibitor of gastric secretion.

Effect of jejunal resection on the gastric acid secretory response to pentagastrin, histamine and feeding in dogs.

In dogs with gastric fistulas and denervated pouches from the oxyntic area, the acid secretory responses to a meal and to graded doses of histamine and pentagastrin were measured before and after resection of the upper half of the small bowel. Intestinal resection caused a small but significant increase in submaximal and maximal response from the pouch to histamine and pentagastrin without modification of the ED50. This effect was not observed in the innervated stomach. The response from the pouch to feeding was markedly increased and prolonged. These data indicate that both an increase in stimulation and an increase of the response to this stimulation are responsible for the increased acid secretion observed in the pouch when resected dogs were fed. These effects could be explained by the withdrawal of inhibitors of intestinal origin.

Synthesis and tissue distribution of four Se-labeled tertiary amines, potential brain pH imaging agents.

Four new tertiary amines: bis(3-N,N-dimethyl aminopropyl)selenide (PROMOSE), bis(3-N-(morpholino)propyl)selenide, N-methyl-selenomorpholine and N-phenyl-selenomorpholine structurally related to MOSE proposed by Kung and Blau, have been labeled through a radiochemical procedure suitable for both 75Se and 73Se. The radiochemical yields of the carrier added synthesis ranged between 64 and 85% for the four 75Se labelings and was 64% EOB time corrected for [73Se]PROMOSE. The chemical and radiochemical purities were higher than 99% after chromatographic purifications. The n-octanol/phosphate buffer partition coefficients (P) were measured at various pH (6.5-8) for each compound and the tissue distributions of PROMOSE in rats were also carried out. The experimental results showed a good correlation between the P = f(pH) function and the in vivo behaviour of the considered compound. PROMOSE was selected for further investigations as a brain pH indicator.

Chemical processing for production of no-carrier-added selenium-73 from germanium and arsenic targets and synthesis of L-2-amino-4-([73Se]methylseleno) butyric acid (L-[73Se]selenomethionine).

The Ge(4He, xn) and 75As(p, 3n) reactions were compared as the best potential routes for routine production of selenium-73 (73Se) for medical applications. With 26 MeV alpha particles, available with compact cyclotrons, the first reaction required an enriched 70Ge target of sodium metagermanate to give a production yield of 1 mCi/microAh (0.037 GBq/microAh) in a 105 mg/cm2 target. With 55 MeV protons the As(p, 3n) reaction on natural arsenic yielded 20 mCi/microAh (0.74 GBq/microAh) in a 685 mg/cm2 target. A simple method was developed and optimized for both targets in order to isolate and purify the no-carrier-added selenium in the elemental form with a radiochemical yield greater than 75% in less than 90 min. An automated radiochemical processing unit has been designed for the routine production of 100-150 mCi (3.7-5.5 GBq) batches of carrier-free 73Se ready for radiopharmaceutical labeling. 30 mCi (1.11 GBq) (EOS) of L-2-amino-4-([73Se]methylseleno) butyric acid (L-[73Se]selenomethionine) ready for injection with a specific activity of 5 Ci/mmol (185 GBq/mmol) (EOS) were obtained through a fast chemical synthesis. Radiation absorbed dose estimates for L-[73Se]selenomethionine have been determined. A value of 0.70 rem/mCi (0.19 mSv/MBq) administered was calculated for the risk from irradiation in man. The first human PET investigation with [73Se]selenomethionine showed a very good delineation between liver and pancreas.

Preparation and evaluation of a hydrous tin(IV) oxide 82Sr/82Rb medical generator system for continuous elution.

Hydrous tin(IV) dioxide in the Na+-form appears to be the most efficient inorganic exchanger for a reliable and versatile clinical 82Rb generator. Continuous elution with a commercial physiological NaCl solution yields 82Rb ranging between 10 and 40% at a flow rate as low as 3 to 10 mL/min respectively. At the same time the Sr breakthrough is less than 1.6 10(-6)%/mL. A clinical generator loaded with 100 mCi 82Sr (150 mCi 85Sr) and continuously eluted for 3 min at a typical flow rate of 5 mL/min yields 40 mCi of 82Rb, 8 nCi of 82Sr and 11 nCi of 85Sr. The total absorbed radiation dose for 40 mCi 82Rb administered is primarily due to 82Rb and has been estimated for the three principal target organs as 760 mrad for the kidneys, 520 mrad for the heartwalls and 276 mrad for the lungs. The 82,85Sr contribution to the dosimetry has been shown to be negligible. The absence of radiolysis with generators loaded with high level of 82Sr was demonstrated by the excellent reproductibility of continuous elution properties of the generator during its practical shelf-life estimated to 5-6 weeks of clinical use which would require more than 30 L of eluent.

Tissue distribution, autoradiography, and metabolism of 4-(2'-methoxyphenyl)-1-[2' -[N-2"-pyridinyl)-p-[(18)F]fluorobenzamido]ethyl]piperazine (p-[(18)F]MPPF), a new serotonin 5-HT(1A) antagonist for positron emission tomography: An In vivo study in rats.

The in vivo behavior of 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-[(18)F]fluorobenzamido ]ethyl]-piperazine (p-[(18)F]MPPF), a new serotonin 5-HT(1A) antagonist, was studied in awake, freely moving rats. Biodistribution studies showed that the carbon-fluorine bond was stable in vivo, that this compound was able to cross the blood-brain barrier, and that a general diffusion equilibrium could account for the availability of the tracer. The great quantity of highly polar metabolites found in plasma did not contribute to the small amounts of metabolites found in hippocampus, frontal cortex, and cerebellum. Exvivo p-[(18)F]MPPF and in vitro 8-hydroxy-2-(di-n-[(3)H]propylamino)tetralin autoradiography were compared both qualitatively and quantitatively. Qualitative evaluation proved that the same brain regions were labeled and that the p-[(18)F]MPPF labeling is (a) in total agreement with the known distribution of 5-HT(1A) receptors in rats and (b) characterized by very low nonspecific binding. Quantitative comparison demonstrated that the in vivo labeling pattern obtained with p-[(18)F]MPPF cannot be explained by differences in regional blood flow, capillary density, or permeability. The 5-HT(1A) specificity of p-[(18)F]MPPF and binding reversibility were confirmed in vivo with displacement experiments. Thus, this compound can be used to evaluate parameters characterizing 5-HT(1A) binding sites in the brain.

191Os/191mIr-generator for studying arterial blood flow in experimental animal models.

Iridium-191m (191mIr, t1/2 = 4.96 sec), an ultra-short lived tracer, has turned out to be suitable for gamma imaging. It can be obtained in high yields from an 191Os/191mIr-generator with a low 191Os breakthrough. In this study the blood flow in the carotid and kidney arteries was studied in rabbits by radionuclide arteriograms. In addition, the whole body retention and biodistribution of 191Os was studied in rats. 191mIr was obtained from an activated carbon system, in a modification of the procedure described in the literature. The kidney regions (study I) of rabbits were imaged dynamically (5 frames/second) for up to 40 seconds, and the investigations were repeated 4-7 times in the same animal. Similarly, the carotid arteries were studied (study II) and from the curves flow parameters were calculated. In order to study the 191Os breakthrough two groups of rats (n = 5) were sacrificed one day and four days after injecting five diagnostic doses into the tail vein (study III). In study III the Os-retention was highest in the kidneys and spleen, followed by the muscles and liver: 0.11-0.12% ID/g tissues were obtained at 1 day and 0.10-0.13% ID/g at 4 days, respectively. These values indicate that the breakthrough values are by no means toxic and that investigations can be repeated immediately with a negligible radiation exposure. The investigations performed with the same animals (I-II) could be easily repeated and were reproducible. All of this indicates that 191mIr is suitable for radionuclide angiography and the generator system is simple and safe to use (191Os is beta-emitter).(ABSTRACT TRUNCATED AT 250 WORDS)