Segmental colonic transit after oral 67Ga-citrate in healthy subjects and those with chronic idiopathic constipation.

UNLABELLED: Measurement of segmental colonic transit is important in the assessment of patients with severe constipation. 111In-diethylenetriamine pentaacetic acid (DTPA) has been established as the tracer of choice for these studies, but it is expensive and not readily available. 67Ga-citrate is an inexpensive tracer and when given orally is not absorbed from the bowel. It was compared with 111In-DTPA in colonic transit studies in nonconstipated control subjects and then in patients with idiopathic constipation. METHODS: Studies were performed after oral administration of 3 MBq (81 microCi) 67Ga-citrate or 4 MBq (108 microCi) 111In-DTPA in solution. Serial abdominal images were performed up to 96 h postinjection, and computer data were generated from geometric mean images of segmental retention of tracer, mean activity profiles and a colonic tracer half-clearance time. RESULTS: There were no differences in segmental retention of either tracer or in mean activity profiles between control subjects and constipated patients. Results in constipated subjects were significantly different from those in controls. The mean half-clearance times of tracer for control subjects were 28.8 h for 67Ga-citrate and 29.9 h for 111In-DTPA in control subjects and 75.0 h for 67Ga-citrate and 70.8 h for 111In-DTPA in constipated patients. CONCLUSION: Oral 67Ga-citrate can be used as a safe alternative to 111In-DTPA for accurate measurement of segmental colonic transit.

Radiolabeling and biodistribution of amiodarone and desethylamiodarone.

The antiarrhythmic drug amiodarone and its metabolite desethylamiodarone, were radiolabeled with sodium [123I]-iodide in > 98% yield using the exchange labeling method. Biodistribution studies with 123I-amiodarone in mice showed high liver and lung uptake. Heart uptake of 0.98% of the injected dose (id) peaked at 5 min, with clearance seen over 60 min to 0.44% id. 123I-Desethylamiodarone (123I-DEA) showed heart uptake of 0.58% id peaking at 5 min, with slower clearance seen over 60 min to 0.43% id. These results indicate that both agents have poor selectivity as myocardial imaging tracers. Low 123I-DEA brain uptake at 5 min (0.49% id) and rapid washout after 60 min indicate that 123I-desethylamiodarone has limited application as a brain imaging agent.

Gallium-67 complexes as radioactive markers to assess gastric and colonic transit.

UNLABELLED: Constipation and gastroparesis are gastrointestinal tract disorders that can be assessed by using radioactive markers in conjunction with scintigraphic techniques. Indium-111-DTPA is the radiopharmaceutical of choice for treating colonic transit in constipated patients, but it is an expensive product and its availability has been unreliable. Indium-113m-DTPA was the tracer used in our study to determine the liquid gastric emptying rate in dual-isotope solid/liquid emptying studies, however, cessation of the 113Sn/113mIn generator production makes it unavailable. Thus, development of alternative tracers to 111In-DTPA and 113mIn-DTPA was essential. METHODS: Gallium-67-citrate and 67-Ga-EDTA were compared to 111In-DTPA to assess their efficacy for exclusive retention in the Gl tract. These markers were orally administered into rats and their three-day cumulative fecal excretion, urine excretion and carcass retention were measured. An in vitro gastric emptying model was used to determine liquid phase partitioning of 113mIn-DTPA, 67Ga-citrate and 67Ga-EDTA at 37 degrees. RESULTS: Gallium-67-citrate was predominantly excreted in the feces (97.2% +/- 0.2%) after three days, with negligible urine excretion (0.1% +/- 0.0%) and carcass retention (0.6% +/- 0.2%). These results are analogous to those obtained for 111In-DTPA for fecal excretion (96.7% +/- 2.6%), urine excretion (0.6% +/- 0.0%) and retention in the carcass (0.2% +/- 0.0%). Gallium-67-EDTA showed similar partitioning in the liquid phase of the gastric emptying model compared with 113mIn-DTPA. CONCLUSION: Gallium-67-citrate is an economical and readily available alternative to 111In-DTPA as a colonic transit radiopharmaceutical. Gallium-67-EDTA is also an alternative to 113mIn-DTPA for assessing liquid-phase emptying in a dual-isotope solid/liquid gastric emptying study.

Radiochemical characterization of modified Technegas.

The aim of this study was to characterize modified Technegas, employing radiochemical analyses and qualitative rabbit organ imaging techniques. Electrophoresis, thin layer chromatography and imaging studies, found modified Technegas to behave like sodium [99mTc]pertechnetate (pertechnetate). Our data indicate that modified Technegas is a pertechnetate aerosol, which results from the presence of 3% oxygen in the reaction atmosphere of the Technegas generator.

Kit preparation of technetium-99m-mercaptoacetyltriglycine: analysis, biodistribution and comparison with technetium-99m-DTPA in patients with impaired renal function.

Technetium-99m-mercaptoacetyltriglycine (99mTc-MAG3) was prepared by a frozen solution method, enabling the preparation of kits yielding a product substantially free of lipophilic impurities (96% 99mTc-MAG3). However, biliary activity was not completely eliminated as HPLC-purified 99mTc-MAG3 was also excreted by that route. Sequential 99mTc-DTPA and 99mTc-MAG3 renal scans were performed in 15 patients with renal dysfunction, including renal transplant recipients. In all cases, the 99mTc-MAG3 kit preparation provided superior images to 99mTc-DTPA at all levels of renal function due to a higher target-to-background ratio and a plasma clearance twice as fast as 99mTc-DTPA. Interpretation of delayed 99mTc-MAG3 images, however, was complicated by biliary excretion which will limit quantitative estimates of renal clearance. A 99mTc-MAG3 kit is likely to be of value in renal transplant assessment and in cases of significant renal impairment but would not appear to offer major advantages over 99mTc-DTPA in routine renal imaging.

Paramagnetic complexes of manganese(II), iron(III), and gadolinium(III) as contrast agents for magnetic resonance imaging. The influence of stability constants on the biodistribution of radioactive aminopolycarboxylate complexes.

Paramagnetic complexes of manganese(II), iron(III), and gadolinium(III) with many ligands appear to undergo ligand substitution in vivo, producing biodistribution data similar to the hydrated metal ions. To identify ligands likely to be valuable in the preparation of paramagnetic contrast agents, a series of aminopolycarboxylate complexes with stability constants increasing in the order iminodiacetic acid (IDA) less than nitrilotriacetic acid (NTA) less than EDTA less than CDTA less than or equal to DTPA was prepared with 54Mn(II), 59Fe(III), and 153Gd(III) at both tracer and carrier levels. Biodistribution studies in mice suggested that complexes remained unchanged in vivo if their stability constants (K1) were approximately greater than 10(16) for Mn(II) and Gd(III) and greater than 10(22) for Fe(III) complexes at tracer levels. Metal complexes with added carrier appeared to be effectively more stable in vivo, possibly due to dissociation and saturation of metal-binding sites. To avoid the accumulation of metal ions in tissues, new paramagnetic contrast agents containing these metal ions will require stability constants equal to or greater than those identified here.

The effect of lipophilic substituents on the biological properties of EDTA complexes containing paramagnetic metal ions.

Complexes of the radioactive paramagnetic metal ions 51Cr(III), 54Mn(II), 59Fe(III), 57Co(II), 64Cu(II) and 153Gd(III) were prepared with EDTA and its derivative containing the lipophilic 1-(4-methylphenyl)-group (MPEDTA), together with the corresponding 99mTc-compounds. The formation of these complexes was verified by electrophoresis and they were screened for potential use as MRI hepatobiliary contrast agents by biodistribution studies in mice. In this series, the MPEDTA complexes of 54Mn(II) and 64Cu(II) showed increased urinary excretion compared to the unsubstituted EDTA complexes, while the MPEDTA complexes of 99mTc, 59Fe, 57Co, 153Gd and particularly 51Cr demonstrated improved hepatobiliary excretion. Further lipophilic substitution should enhance this property but the preparation of such ligands is complicated by cyclisation reactions.

A comparison of radiolabelled agents for thrombus imaging using a rabbit model.

The quantitative uptakes of five potential thrombus-localizing radiopharmaceuticals in experimental thrombi of the rabbit jugular vein have been compared to assist with the selection of a thrombus imaging agent for clinical use. Three hours after injection, 111In-platelets were clearly the agent of choice but at 18 h 99mTc-fibrinogen had more favourable characteristics. Both agents were superior to 99mTc-plasmin or its acyl derivatives, including 99mTc-streptokinase-activated anisoylplasminogen. The ease of preparation coupled with favourable biological properties suggest that 99mTc-fibrinogen should be of value in the clinical situation.

The preparation of 99mTc-tertiarybutylisonitrile (99mTc-TBI) by a method suitable for routine clinical use.

The myocardial imaging agent technetium-99m-hexakis (tertiarybutylisonitrile) (99mTc-TBI) was prepared by the reaction of [99mTc]pertechnetate with TBI in 50% ethanol/0.9% saline at 100 degrees C, using stannous chloride as the reducing agent. A study of the reaction parameters enabled the yield to be optimized to better than 90%, although this was reduced to approximately 60% if a purification step was carried out. Chromatographic analysis on ITLC-SG medium showed the final product to be of high radiochemical purity. Biological studies comprising biodistribution in mice over a 2-h period, imaging studies in animals and sub-acute toxicity testing in mice indicated that 99mTc-TBI prepared as here described is a suitable agent for routine clinical use in humans.

Studies of 99mTc-acylplasmins as agents for thrombus detection.

It has been proposed that acylation at the active site of plasmin is able to prevent its reaction with alpha 2-antiplasmin without affecting the fibrin affinity of the enzyme. To investigate the possibility that 99mTc-labelled acylplasmins are improved thrombus-detecting agents, six acylating agents were synthesised and their reaction with plasmin and the labelling of the products with 99mTc studies. Uptake of 99mTc-acylplasmins in an in vitro thrombus model was complicated by precipitation processes, which may in part account for the rapid blood clearance in rabbits and high liver uptake in mice injected with the compounds. Quantitative measurements using an in vivo rabbit thrombus model demonstrated that guanidinobenzoyl-plasmin exhibited nearly a threefold increase in thrombus uptake compared with non-acylated 99mTc-plasmin. The observed uptake is less than that obtained with 125I-fibrinogen at clinically useful time intervals post-injection but represents a significant advantage over the use of 99mTc-plasmin.

Technetium-99m calcium phytate--optimization of calcium content for liver and spleen scintigraphy: concise communication.

The addition of ionic calcium to technetium-99m stannous phytate produced an agent with improved splenic uptake. In a series of patients, it was found that molar ratios of 2:1 and 3:1 produced scans of optimal diagnostic quality. Studies in mice showed dose-related changes in the biodistribution. Electron microscopy demonstrated that the addition of calcium produced progressive aggregation of the colloid as the molar ratio was increased. Chemical analysis of sodium phytate was essential to obtain accurate ratios.

Technetium 99m-pyridoxylideneglutamate: a new hepatobiliary radiopharmaceutical. I. Experimental aspects.

The labeling of pyridoxal and the pyridoxylidene derivative of glutamic acid with 99mTc has been achieved by a simple autoclaving procedure. Technetium-99-m-pyridoxylideneglutamate (99mTc-PG) shows marked biliary excretion with accumulation of radioactivity in the gallbladder and intestines of experimental animals. This compound has been extensively investigated with a view to its application in the diagnosis of biliary disorders in man by scintigraphy. Both scintigraphic and quantitative distribution studies showed that 99mTc-PG passed rapidly through the mouse liver with progressive accumulation in the gallbladder, allowing visualization of this organ within 10 min of injection. In 30 min over 40% of the injected dose was excreted into the intestine with an equivalent amount appearing in the urine; however, renal activity remained low. Scintigraphic studies in dogs showed results similar to those obtained in mice. Studies of the toxicity in three animal species indicated a wide margin of safety for 99mTc-PG in the dose proposed for diagnostic purposes in humans.

Technetium-99m-pyridoxylideneglutamate: a new hepatobiliary radiopharmaceutical. II. Clinical aspects.

Technetium-99m-pyridoxylideneglutamate (99mTc-PG) is a nontoxic radiopharmaceutical that was found to undergo rapid biliary excretion in normal humans. The biliary tree and gallbladder were seen within 10-15 min of injection and by 20 min marked accumulation of radioactivity was noted in the gallbladder and gastrointestinal tract. Of ten "control" volunteers, seven had normal 99mTc-PG-cholescintigrams. In the remaining three, the gallbladder was not visualized. Gallbladder disease was not excluded in these three subjects. Of 24 patients referred for investigation of right upper quadrant abdominal pain, 13 proved to have gallbladder disease. All seven patients with acute cholecystitis and one of four patients with chronic cholecystitis had nonvisualization of the gallbladder on the cholescintigram whereas five patients with chronic cholecystitis or cholesterolosis had normal cholescintigrams. Six of the eight patients with nonvisualization of the gallbladder on cholescintigram had contrast radiologic studies (oral cholecystogram or intravenous cholangiogram or both), and in all six, nonvisualization of the gallbladder was also reported on the contrast study. cholescintigraphy was found to be greatly inferior to contrast radiologic studies in the detection of gallbladder stones. Eleven patients had complete extrahepatic biliary obstruction and this diagnosis was correctly made in all 11 by the cholescintigram. Fourteen patients had incomplete extrahepatic biliary obstruction. The correct diagnosis was made on the cholescintigram in seven but in the remaining seven it was not possible to distinguish between incomplete extrahepatic biliary obstruction and hepatocellular disease. Malignant lesions (carcinomas of head of pancreas, gallbladder, common bile duct or ampulla of Vater) were the cause of obstruction in 10 of the 25 patients with complete or incomplete obstruction and the diagnosis of obstruction due to malignancy was correctly made in 8 of these 10 by means of a scintigraphic equivalent to Courvoisier's sing. Finally, 11 patients had hepatocellular disease and a nonspecific pattern consistent with either imcomplete biliary obstruction or hepatocellular disease was observed on the cholescintigram in all 11. The 99mTc-PG cholescintigram is suggested for a role complementary to that of contrast radiologic studies in the preoperative investigation of patients with possible surgical disease of the biliary tract. Contrast radiologic techniques are advocated as being more appropriate in the nonjaundiced patient with suspected gallbladder disease whereas the 99mTc-PG cholescintigram is advocated as being more appropriate in the patient with jaundice. The value of the 99mTc-PG cholescintigram lies in the confidence with which complete extrahepatic biliary obstruction can be diagnosed. The "scintigraphic Courvoisier's sign" seems a useful indicator of malignant obstruction.