Bromine-80m-labeled estrogens: Auger electron-emitting, estrogen receptor-directed ligands with potential for therapy of estrogen receptor-positive cancers.

To assess their possible use for estrogen receptor (ER)-directed radiotherapy of estrogen receptor-containing cancers, two estrogens were synthesized with the Auger electron-emitting nuclide bromine-80m and administered to immature female rats. Both the triphenylethylene-based estrogen, [80mBr]-2-bromo-1,1-bis(4-hydroxyphenyl)phenylethylene (Br-BHPE) and the steroidal estrogen [80mBr]17 alpha-bromovinylestradiol, showed substantial diethylstilbestrol-inhibitable localization only in the estrogen target tissues, the uterus, pituitary, ovaries, and vagina and, except for the liver and intestines, generally lower concentrations in all other tissues at both 0.5 and 2 h. The [80mBr]Br-BHPE (specific activity, 8700 Ci/mmol), was shown to bind specifically to the low salt extractable ER of the rat uterus. Comparing i.p., i.v., and s.c. administration of [80mBr]BHPE the i.p. route was found to be particularly advantageous to effect maximum, DES-inhibitable concentrations of radiobromine in the ER-rich target organs in the peritoneal cavity. When the tissue distribution of the [80mBr]Br-BHPE was compared with that of sodium bromide-80m, it was apparent that no substantial amounts of radiobromine were released from the bromoestrogen prior to its target tissue localization. The substantial concentration of these bromine-80m-labeled estrogens in ER-rich tissues, combined with previously reported evidence for the effective radiotoxicity of Auger electron-emitting nuclides within cell nuclei suggest a good potential for such ligands for therapy of ER positive cancers.

Bromine-80m radiotoxicity and the potential for estrogen receptor-directed therapy with auger electrons.

While theoretically feasible, estrogen receptor (ER)-directed radiotherapy of hormone-dependent cancers has not been realized because no ER-seeking ligand with an appropriate radiotoxic potential has been identified. Since an appropriate nuclide is a key component we studied the 4.4-h half-life, Auger electron-emitting nuclide bromine-80m. When incorporated into DNA this nuclide was radiotoxic to cells in culture and caused substantial chromosomal damage, while similar concentrations of bromine-80m as bromide or bromoantipyrine were without effect. The mean lethal dose for bromine-80m was 45 atoms per nucleus which is consistent with use in receptor-positive cancers with limited numbers of ER.

Accumulation of technetium-99m pyrophosphate in experimental infarctions in the rat.

Cardiac accumulation patterns of pyrophosphate labelled with techetium-99m (TcPyP) in rats one hour to 7 days after coronary artery ligation were studied by light microscopy, myocardial scintigraphy, imaging the isolated heart and by direct measurement of tissue activity. Results suggest that myocardial cells taking up TcPyP are irreversibly damaged and that the disappearance of TcPyP uptake coincides with the removal of necrotic cells by phagocytes.

Comparison of the distribution of bromine-77-bromovinyl steroidal and triphenylethylene estrogens in the immature rat.

The specific uptake and distribution of steroidal and non-steroidal [77Br]bromovinylestrogens were studied in immature female rats to assess the potential of these radioligands for imaging or therapy of estrogen receptor (ER) positive cancers. E-17 alpha [77Br]bromovinylestradiol, its 3 methyl ether and 11 beta-methoxy derivative, as well as the triphenylethylene estrogen, 1,1-bis[4-hydroxy-phenyl]-2-[77Br]bromo-2- phenylethylene all showed diethylstilbestrol inhibitable, specific uptake of radiobromine between 2 and 16 hr after i.p. administration. The highest concentrations in the estrogen target tissues and the highest target tissue-to-blood ratios were found with E-17 alpha-[Br]bromovinyl-11 beta-methoxyestradiol, but it also had rather high nonspecific uptake in all tissues. The triphenylethylene estrogen showed comparable specific uptake in estrogen target tissues to 17 alpha [77Br]bromovinylestradiol at 2 hr but better apparent retention, indicated by higher specific target tissue levels at the later time points. Thus, [77Br]bromovinyl-11 beta- methoxyestradiol and 1,1-bis[4-hydroxyphenyl]-2-[77Br]bromo-2-phenylethylene appear most favorable for these applications.

Nuclear imaging analysis of human low-density lipoprotein biodistribution in rabbits and monkeys.

We have evaluated the biodistribution of human low-density lipoprotein (LDL) radiolabeled with 99mTc or with 123I-tyramine cellobiose in rabbits and in rhesus monkeys. Biodistribution was assessed after intravenous injection of radiolabeled LDL by quantitative analysis of scintigrams, counting of excreta, and counting of tissues at necropsy. Both rabbits and monkeys showed lower renal uptake (123I:99mTc approximately 1:3, as regional percent injected activity corrected for physical decay) and excretion (1:2 to 1:4), but higher hepatic (1.5:1 to 2:1) and cardiac (1.7:1 to 4:1) uptake of 123I than of 99mTc. Adrenals were visualized in normolipemic animals with 123I-tyramine cellobiose-LDL but not with 99mTc-LDL. Hyperlipemic animals showed increased cardiac (up to six-fold) and decreased hepatic activity (by 50%-60%) of both radionuclides. We conclude that 123I-tyramine cellobiose-LDL is better suited than 99mTc-LDL for dynamic studies of LDL metabolism in vivo.

Positron emission tomography for the evaluation of pancreatic disease.

Efficient techniques for native-labeling of amino acids have been combined successfully with emission tomography to yield significant improvements in pancreatic imaging. Carbon-11-labeled tryptophan appears to be the best agent available currently for imaging the pancreas. Optimum scanning times begin 30 min after tracer administration. Positron emission tomography with 11C-tryptophan is capable of defining both morphological and functional alterations in the pancreas. Tumors as small as 2 cm in diameter can be detected, but reliable differentiation of pancreatic cancer from pancreatis may not be possible even with this improved imaging technique. Longitudinal multiplane emission tomography in single-photon mode with the Pho/Con provides an efficient and satisfactory approach to pancreatic imaging with the positron-emitting radiopharmaceuticals.

Nitrogen-13-labeled ammonia for myocardial imaging.

Cyclotron-produced nitrogen-13 (half-life 10 min), as labeled ammonia (13NH4+), has been evaluated as a myocardial perfusion imaging agent. The regional myocardial uptake of 13NH4+ has been shown to be proportional to regional tissue perfusion in animal studies. Intravenously administered 13NH4+ is rapidly cleared from the circulation, being extracted by the liver (15%), lungs, myocardium (2%-4%), brain, kidney, and bladder. Myocardial ammonia is metabolized mainly to glutamine via the glutamine synthetase pathway. Pulmonary uptake is substantial, but usually transient, except in smokers where clearance may be delayed. The position annihilation irradiation (511 keV) of 13N may be imaged with a scintillation camera, using either a specially designed tungsten collimator or a pinhole collimator. After early technical problems with collimation and the production method of 13NH4+ were overcome, reproducible high quality myocardial images were consistently obtained. The normal myocardial image was established to be of a homogeneous "doughnut" configuration. Imaging studies performed in patients with varying manifestations of ischemic and valvular heart disease showed a high incidence of localized perfusion defects, especially in patients with acute myocardial infarction. Sequential studies at short intervals in patients with acute infarction showed correlation between alterations in regional perfusion and the clinical course of the patient. It is concluded that myocardial imaging with 13NH4+ and a scintillation camera provides a valid and noninvasive means of assessing regional myocardial perfusion. This method is especially suitable for sequential studies of acute cardiac patients at short intervals. Coincidence imaging of the 511 keV annihilation irradiation provides a tomographic and potentially quantitative assessment of the regional myocardial uptake of 13NH4+.

Accumulation of indium-111-labeled human low density lipoprotein in the rabbit aorta: Implications for nuclear imaging of vascular lesions.

Nuclear imaging of atheromata must distinguish lesions from both blood pool and normal arterial tissue. We have examined spatial and temporal variations of indium-111-labeled human low density lipoprotein (LDL) accumulation in rabbit aortas. LDL-derived In-111 activity was time-independent in lesion-resistant regions of aortas from normal and hypercholesterolemic animals (mean 2.9 × 10(-6) percent injected activity per milligram tissue [%IA/mg]) and in lesion-prone regions of normal aortas (mean 7.1 × 10(-6) %IA/mg). In contrast, activity in sudanophilic lesions of hypercholesterolemic rabbit aortas reached a peak of 31 × 10(-6) %IA/mg at 92 hours postinjection. The mean ratio between activity in lesions versus lesion-resistant regions described a broad convex curve with minima of 4:1 at 14 hours and 136 hours and a peak of 14:1 measured at 72 hours postinjection. The mean ratio between In-111 in lesions and blood followed a sigmoid curve, rising exponentially from 1:25 at 14 hours to 1:3 by 72 hours postinjection. We conclude that optimal signal-to-noise ratios for monitoring atheroma-associated LDL-derived radioactivity occur late, not before about 3 days postinjection. Therefore, LDL labeled with In-111 or even longer-lived radionuclides holds the greatest promise for effective clinical nuclear imaging of atherosclerosis.

In vitro calculation of flow by use of contrast ultrasonography.

Contrast echocardiography has been used for qualitative assessment of cardiac function, and its potential for quantitative assessment of blood flow is being explored. With the development of an ultrasound contrast agent capable of passage through the microcirculation, a mathematical model based on classic dye dilution theory, and a digital ultrasound acquisition system, absolute quantitation of myocardial perfusion may be feasible. This study validates the mathematical model in a simple in vitro tube system. Flow was delivered at variable rates through an in vitro tube system while a longitudinal section was imaged with a modified commercial ultrasound scanner. Albunex contrast agent was injected, and videointensity data were captured and analyzed off line. Time-intensity curves were generated, and flow was calculated by use of a mathematical model derived from classic dye dilution mathematics. For 39 different flow rates, ranging for 9.2 to 110 ml/seconds, a correlation coefficient of r = 0.928 (p < 0.001) with a slope of 0.97 was calculated. We conclude that (1) contrast ultrasonography is capable of quantitative determination of flow in an in vitro system, and (2) a mathematical model based on dye dilution theory can be used to calculate flow with accuracy and precision.

Multiparameter extrapolation of biodistribution data between species.

Values of an inaccessible biological parameter in man may be predicted from values measured in animals by correlating with a parameter accessible in both species, such as body weight, energy production, excretion rate, etc. Predicting toxic effects, from environmental chemicals, of therapeutic doses for drug administration and of radiation absorbed dose from medical and environmental radioactivity depends on the rationalization of relationships between concentration and time when scaling to humans from animal data. For example, the retention of 99mTc, injected intravenously as pertechnetate, reaches 10% in the mouse at about 1 d, but this level occurs in humans at about 7 d. Making a simultaneous transformation between two species for the concentration and time variables by using a method of least-squares fitting, we have derived a series of transformation factors for several species. When correlated with a biological parameter such as body weight, these factors can be used to yield predicted values that are in good agreement with measured values. This system may be used with any related variables, making it useful for predicting other types of biological data.