Physicochemical properties, pharmacokinetics, and biodistribution of gadoteridol injection in rats and dogs.

RATIONALE AND OBJECTIVES: The physicochemical properties of gadoteridol, a macrocyclic nonionic gadolinium complex, were studied together with its pharmacokinetics and biodistribution in rats and dogs. METHODS: Studies in rats were conducted after single intravenous injections at 0.1 or 0.35 mmol/kg using 153Gd-labeled gadoteridol or with seven daily doses of 0.1 mmol/kg to examine the levels of residual gadolinium in organs. Nonradioactive biodistribution and excretion studies were performed in dogs following injection at 0.1 mmol/kg. RESULTS: After injection, the dose was rapidly cleared from rat blood and excreted such that more than 90% of the dose appeared in the urine within 4 hr of injection. At 7 and 14 days postinjection, only extremely low levels of gadolinium were observed in liver and bone; these levels were two to eight times lower than the levels reported after the injection of gadopentetate dimeglumine. CONCLUSION: The extracellular distribution and rapid urinary excretion of gadoteridol is in agreement with data obtained with other gadolinium-containing chelates used as intravascular magnetic resonance imaging contrast agents. Differences observed in the long-term retention of gadolinium between gadoteridol and gadopentetate dimeglumine were consistent with the reported greater in vivo resistance to transmetallation of gadolinium macrocycles compared with the linear gadolinium chelate molecules.

Phase I clinical evaluation of a new iron oxide MR contrast agent.

The safety and magnetic resonance (MR) imaging potential of BMS 180549, a new superparamagnetic iron oxide contrast agent, were evaluated in a phase I, open-label, placebo-controlled study involving 41 healthy subjects. No clinically significant postdose changes in physical examination findings, vital signs, or electrocardiogram results were reported for any of the subjects evaluated. No clinically significant changes in clinical laboratory values were noted by the investigators. Fourteen adverse events considered not serious and considered possibly or definitely related to the drug were reported, three of which required minor treatment. Relaxation time measurements in plasma samples showed a strong, dose-dependent, and persistent decrease in T1 and T2 values. Significant changes in MR signal intensity of the blood pool and well-perfused organs (liver and spleen) were noted on both T1- and T2-weighted images. Changes in signal intensity of cervical lymph nodes were also observed at the higher doses and late postdose imaging times.

Preparation of [1-11C]acetate--an agent for the study of myocardial metabolism by positron emission tomography.

A method of obtaining an injectable solution of acetate labelled in the carboxyl group with the short-lived positron-emitting radionuclide, 11C (t12 = 20.4 min), is described. In the method labelling is achieved via the carbonation of freshly prepared methylmagnesium bromide with 11C-labelled carbon dioxide produced by the 14N(p, alpha)11C nuclear reaction. The method is fast (20 min) and produces sterile, apyrogenic [1-11C]acetate in high radiochemical yield (72 +/- 12%) and in high specific activity (greater than 18.5 GBq/mumol: greater than 0.5 Ci/mumol). The radiochemical purity of the radiopharmaceutical was found to exceed 95% by thin layer and high pressure liquid chromatography. Evidence presented shows that [1-11C]acetate has considerable value as an agent for investigating myocardial metabolism by positron emission tomography.

Subcellular localization of 111In in human and rabbit platelets.

In order to examine the subcellular distribution of 111In in 111In-oxine-labeled human and rabbit platelets, we employed a hypothetical grain technique of EM autoradiography analysis. The results indicate that in the rabbit 111In was concentrated within the platelet dense bodies, particularly when the platelets had been labeled in a plasma-free system. Under comparable conditions of labeling, human platelets appeared to accumulate almost all the radiolabel within the cytosol. Using inhibitors of 5-hydroxytrptamine (5-HT) uptake, i.e., cloimipramine, ouabain, sodium fluoride, p-chloromercuribenzoate, and reserpine, we were unable to demonstrate an active uptake process in either species. Both collagen and thrombin were able to cause dose-dependent release of radioactivity from the labeled rabbit platelets only. In the case of collagen, this mimicked endogenous 5-HT release and was inhibited by indomethacin. These results and their implications are discussed.

Oscillations in tissue uptake of 75Se-L-selenomethionine in rats and mice adapted to controlled feeding schedules.

The amino acid 75Se-L-selenomethionine was used to study variations in amino acid uptake by various tissues of rats and mice adapted to a schedule of controlled feeding and lighting conditions. Food only became available for an 8-hour period at the beginning of the 12-hour dark period of the 24-hour cycle. Systematic oscillations were observed in the uptake of selenomethionine by the liver, pancreas, blood, kidneys, skeletal muscle, bone and brain of both rats and mice but only very small changes were noted in the spleen, lung and heart. The level of the uptake into the liver and pancreas and possibly the kidney appear to be related to the dietary state of the animals.

The distribution of 75Se-adenosyl selenomethionine in the rat with observations on its potential as a prostate scanning agent.

The preparation of 75Se-adenosyl selenomethionine is described. Following injection into male rats 63% of the administered label was excreted in 24 h, predominantly in the urine. The remaining activity appeared to have joined the S-adenosyl methionine pool residing mainly in the liver and kidney. The maximum incorporation into the ventral prostate was 2 to 4 h after injection at 0.7% injected dose/g wet weight. These results indicate that 75Se-adenosyl selenomethionine is not a suitable radiopharmaceutical for diagnostic scanning of the prostate.