P. Som

A Fluorinated Glucose Analog, 2-fluoro-2-deoxy-D-glucose (F-18): Nontoxic Tracer for Rapid Tumor Detection

Rapid uptake of F-18 FDG was observed in a variety of transplanted and spontaneous tumors in animals. The tumor uptake reached a peak by 30 min and remained relatively constant up to 60 min, with a very slow wash-out of F-18 activity from the tumor thereafter. Tumor-to-normal tissue and tumor-to-blood ratios ranged from 2.10-9.15 and 2.61-17.82, respectively, depending on the type of tumor. A scintiscan of a seminoma in a dog showed very high uptake in the viable part and lack of uptake in the necrotic mass. Toxicological studies in mice using 1000 times human tracer dose (HTD) per wk for 3 wk and in dogs using 50 times HTD per wk for 3 wk did not show any evidence of acute or chronic toxicity.

Cell attachment and biocompatibility of polytetrafluoroethylene (PTFE) treated with glow-discharge plasma of mixed ammonia and oxygen

The plasma generated from a gas mixture of NH3 plus O2 (NH3 + O2) has been used to impart unique chemical and biological characteristics to polytetrafluoroethylene (PTFE). PTFE treated with NH3 + O2 plasma was physiochemically distinct from surfaces treated with plasma of either NH3 or O2 alone, as determined by electron spectroscopy for chemical analysis (ESCA). The contact angle analysis revealed that the PTFE surfaces became less hydrophobic after plasma treatments. ESCA results indicate the presence of oxygen-containing groups and nitrogen-containing groups at the plasma-treated surfaces. PTFE treated with NH3 + O2 plasma resisted the attachment of platelets and leukocytes in a manner similar to untreated PTFE; however, the attachment of bovine aorta endothelial cells was substantially increased. Once attached, these cells grew to confluency. The increased endothelial cell attachment was higher than that observed following plasma treatment with each gas used separately, which could be attributed to the considerable amount of CF(OR)2-CF2 formed on the NH3 + O2 plasma-treated PTFE surface. At 14 days after subcutaneous implantation in rats, the PTFE wafers treated with NH3 + O2 plasma demonstrated less encapsulation and lower levels of inflammatory cells compared to controls. Collectively, the results suggest that NH3 + O2 plasma treatment imparts a unique character to PTFE and could be useful in certain in vivo applications.

The development and in-vivo behavior of tin containing radiopharmaceuticals—I. Chemistry, preparation, and biodistribution in small animals☆

Tin is an essential ingredient of most technetium-99m radiopharmaceutical preparations but its in-vivo distribution and long-term fate are not well understood. Tin-117m (t1/2 14d; gamma 159 keV, 86%) is an ideal tracer for studying biological behavior of tin compounds as well as for developing clinically-useful radiopharmaceuticals. This work describes the preparation and in-vivo distribution in mice of a number of tin-117m labeled compounds with commonly used ligands. High bone uptake of most compounds studied as well as the unexpectedly high bone uptake of Sn4+-DTPA indicates a high bone affinity of tin bound to chemically diverse ligands. Various compounds show subtle but significant differences in blood clearance, excretion, and soft-tissue uptake. Differences among Sn2+ and Sn4+ compounds with the same ligand are particularly noteworthy. For stannic chelates, higher bone uptake, faster blood clearance, and reduced soft-tissue concentration were observed. It appears that tin compounds bind to bone predominantly through the tin atom and that the differences in biodistribution depend on factors such as the net charge on the complex, the oxidation state of tin, and hydrolytic and kinetic stabilities of the complexes. The results indicate that the favorable half-life and decay characteristics of tin-117m in various stannic compounds, especially stannic-DTPA, make it potentially useful as an agent for skeletal scintigraphy and radiotherapy of bone tumors.

Myocardial Positron Tomography with Manganese-52m

The biodistribution of radiomanganese (54Mn) was studied in mice, rats, and dogs. Disappearance of radioactivity from the blood was extremely rapid, with a half-time of approximately 0.8 minutes. This resulted in very favorable myocardium-to-blood ratios, even at early times after administration. The myocardial uptake in dogs was greater than 3% at three and 15 minutes, with myocardium-to-blood ratios of about 40:1 at 15 minutes. Positron tomograms obtained with 52mMn clearly demonstrated regional myocardial perfusion. There was good correlation (r = 0.89) of microsphere-to-radiomanganese distribution in the infarcted dog heart.

97Ru-transferrin uptake in tumor and abscess.

The uptake of97Ru-transferrin (Ru-TF) in tumor and abscess bearing animals was compared with67Ga-citrate (Ga),123I-transferrin (I-TF), and several other plasma proteins. Maximal concentration in tumor of Ru-TF in mice was three times higher than67Ga-citrate (16.80±4.20 vs 5.08±0.58% D/g) although it occurred later (24 h compared with67Ga which reached its maximum 2 h after injection). Whole body autoradiography (WBARG) with103Ru-transferrin (103Ru-TF) in tumor and abscess bearing rats demonstrated details of the distribution within these lesions. Turpentine-induced abscesses in the rabbits could be visualized with the gamma camera as early as 30 min post-injection of Ru-TF. It seems, therefore, that Ru-TF can be used for tumor and abscess localization. The results indicate that Ru-TF may have some advantages over67Ga-citrate because of the higher concentration in the lesions.123I-transferrin reached a concentration in tumor similar to67Ga (6.89±1.67 vs 5.08±0.58% D/g) but had a very low tumor to blood ratio (0.64). The three compounds investigated (Ru-TF, I-TF and ionic Ga, which binds instantaneously to TF in vivo) have a common lignad, transferrin. It appears, therefore, that tumor affinity is a property of the radionuclide-ligand complex rather than of the radionuclide itself.

Distribution of 18F-5-fluorouracil in tumor-bearing mice and rats.

Extensive distribution studies of 18F-5-fluorouracil (18F-5-FU) in control and tumor-bearing mice (seven lines) and rats (eight lines) that have been shown or suspected to be responsive; to 5-FU treatment were investigated with 18F-5-FU. Studies were performed as a function of time, loading dose of 5-FU, and after a pretreatment regimen of 5-FU. Following the parenteral administration of 18F-5-FU to tumor-bearing mice and rats there was slight preferential uptake by some of the tumor types, particularly subcutaneous leukemic tumors and breast adenocarcinomas. The degree of concentration in tumor tissue in comparison with surrounding tissues (blood, muscle) was not such as to consider the radiopharmaceutical suitable for tumor localization. However, sufficient amounts of radioactivity localized in some tu,ors so that it might be possible to determine if a correlation exists between tumor uptake and anti-tumor effect of 5-fluorouracil. Another possible area of use might be in regulating the method of administration of the chemotherapeutic agent.

Studies of a new fatty acid analog (DMIVN) in hypertensive rats and the effect of verapamil using ARG microimaging

Studies of myocardial utilization of fatty acids and analogs has focused on coronary heart disease. This study addresses the topic of radioiodinated fatty acid utilization in hypertensive-cardiomyopathy. The new fatty acid analog 19-iodo-3,3-dimethyl-18 nonadecenoic acid (DMIVN) was studied by autoradiographic microimaging (ARG) in salt-sensitive (S) hypertensive (salt-fed) and in salt-sensitive (S) normotensive (low-salt diet), Dahl-strain rats. A salt fed, S-strain group was treated with verapamil and the results were compared to those in a hypertensive, non-treated group. The distribution of DMIVN in the hearts of normotensive rats was uniform. In the myocardium of hypertensive rats nonuniform DMIVN concentration was seen in the subendocardial and mid-layers of the left ventricle (LV). Verapamil given to salt-fed rats prevented hypertension and uniform DMIVN uptake similar to normotensive controls was seen. The data suggest that DMIVN may be suitable for the detection of hypertension induced myocardial changes and for assessing therapy. The distribution and clearance characteristics of DMIVN indicate that DMIVN may be a useful agent for SPECT imaging in man.

Radiolabeling brachytherapy sources with re‐188 through chelating microfilms: Stents

Rhenium-188 (Re-188, T(1/2) = 17 h) emits beta particles (E(max) = 2. 12 MeV) having an ideal range for intravascular brachytherapy and certain cancer brachytherapies. Re-188 was attached to metal wafers and stents via a chelating microfilm, and these brachytherapy sources characterized in vitro and in vivo. To prepare the sources, a siloxane film containing reactive amines was plasma deposited on the metal, a chelating microfilm conjugated to the amines, and the chelating microfilm used to attach Re-188. Re-188 was selectively bound to materials coated with the chelating microfilm. Binding correlated with the amount of radionuclide used. Wafers (1 cm(2)) bound up to 62.9 MBq (1.7 mCi) of Re-188 with yields generally near 30%. Stents bound up to 26.6 MBq (720 microCi). Typically, stents were labeled to bind 4-12 MBq and deposit 10-30 Gy at 2 mm in the arterial wall. In phantom studies, the longer nitinol stents deposited doses of 2.3 Gy/MBq (0.085 Gy/microCi), while shorter stainless steel stents deposited 4.62 Gy/MBq (0.171 Gy/microCi). After placement in arteries of pigs, only the Re-188-stents were detected by scintigraphy at times up to 24 h. Scintigraphy did not detect activity in other organs. Blood sampling (0.1-24 h) detected maximum radioactivity (up to 388 cpm/mL/100micro Ci) at 6 h. We conclude that on-demand radiolabeling of stents and other brachytherapy sources with Re-188 can be performed routinely.

The role of factor analysis in the evaluation of new radiopharmaceuticals

Factor analysis of dynamic scintigraphic studies has been proposed for a variety of clinical applications. This method also called FADS (Factor Analysis of Dynamic Structures) enables spatial separation of complex images into discrete factors according to their time/activity characteristics. FADS, which does not require a priori formulation of a compartmental model of tracer kinetics, is particularly suitable for the evaluation of new radiolabeled compounds as potential radiopharmaceuticals. In animals as well as in humans it is possible to obtain information on the spatial time-distribution of tracers by analyzing computer acquired scintigraphic studies. On the basis of data obtained and analyzed with this method using [123I]IMP in humans, dogs, rabbits and rats, with two 99mTc labeled monoclonal antibodies in dogs and with 99mTc DTPA in renal transplants, we recommend this method as an adjunct in radiopharmaceutical development and evaluation.

Whole-body autoradiographic localization of [3H]phencyclidine and its metabolites in mice

When evaluated by whole-body autoradiography (WBAR) and quantitative densitometry, [3H]phencyclidine (PCP) equivalents were found to be removed rapidly from blood, after a single iv dose in mice, and avidly taken up as early as 1 min after dosage by glandular tissues including thyroid, salivary glands, pancreas, pituitary and, most prominently, by stomach mucosa. Stomach:blood [3H]PCP concentration ratios showed that rapid secretion of [3H]PCP from mucosa to the stomach contents occurred within 2 min after dosing. During early intervals, chromatographic analysis of tissue sections demonstrated that PCP was present in brain, liver, and gut primarily in its unaltered chemical form. Mice killed at 60 and 120 min showed persistently high levels of [3H]PCP equivalents within the stomach and intestines, these levels being the highest of all other tissues densitometrically measured. The early time course and magnitude of [3H]PCP uptake by stomach glandular mucosa strongly suggests that cycling of PCP occurs principally through gastroenteric recirculation. Very striking was the high concentration of [3H]PCP radioactivity observed within the adrenal as early as 5 min. The concentration of [3H]PCP equivalents in pituitary, choroid plexus, cortex, hippocampus, and thalamus was highest at 1-20 min following injection. Application of high-resolution quantitative WBAR was found to be a useful tool in the study of the biodistribution of labeled PCP, especially during very early post-treatment time points where alternative tissue counting techniques would not be feasible.