New selenium-75 labeled radiopharmaceuticals: selenonium analogues of dopamine.

Selenium-75 labeled selenonium analogues of dopamine, [2-(3,4-dimethoxyphenyl)ethyl]dimethylselenonium iodide (4) and its dihydroxy analogue (7), were prepared by reducing [75Se]selenious acid with sodium borohydride at pH 6.0 and reacting the NaSeH produced with 1-(3,4-dimethoxyphenyl)-2-(p-toluenesulfonyloxy)ethane. Tissue distribution studies in rats given the 75Se-labeled selenonium agents intravenously demonstrated high initial heart uptake (2.38% dose/g at 5 min). Prolonged adrenal retention (t1/2 = 10 h) and high adrenal to blood ratio of compound 4 (21/1 at 4 h after injection) were observed. The high uptake and adrenal to blood ratio suggest the potential use of compound 4 as a radiopharmaceutical for the adrenal gland.

Synthesis and ligand binding studies of 4'-iodobenzoyl esters of tropanes and piperidines at the dopamine transporter.

Four analogs and two homologs of cocaine, designed as potent cocaine antagonists, were synthesized. The SN2 reaction between ecgonine methyl ester (13) or appropriately substituted piperidinol (19, 21) and appropriately substituted 4-iodobenzoyl chloride gave 4-iodobenzoyl esters of tropanes and piperidines (5-8). 2'-Hydroxycocaine (9) was obtained from 2'-acetoxycocaine (12) by selective transesterification with MeOH saturated with dry HCl gas. 2'-Acetoxycocaine (12) was synthesized from acetylsalicyloyl chloride (23) and ecgonine methyl ester (13). The binding affinities of these compounds were determined at the dopamine transporter for the displacement of [3H]WIN-35428. An iodo group substitution at the 4'-position of cocaine decreased dopamine transporter binding potency, while a hydroxy or acetoxy group at the 2'-position exhibited increased binding potency for the dopamine transporter compared to cocaine (10- and 3.58-fold, respectively). 2'-Hydroxylation also enhanced the bidning potency of 4'-iodococaine (5) by 10-fold. Replacement of the tropane ring with piperidine led to poor binding affinities.

2beta-Substituted analogues of 4'-iodococaine: synthesis and dopamine transporter binding potencies.

A series of 2beta-substituted analogues of 4'-iodococaine (3) was synthesized and evaluated in an in vitro dopamine transporter (DAT) binding assay. Selective hydrolysis at the 2beta-position of 3 gave the carboxylic acid 15 that served as the intermediate for the synthesis of compounds 4, 5, and 6-11. The 2beta-alkyl derivatives were obtained from ecgonine methyl ester (17) through a series of reactions leading to the aldehyde 20. Wittig reaction of 20 with methyltriphenylphosphorane followed by hydrogenation and benzoylation gave the products 12 and 13. The binding affinity of 4'-iodococaine (3) was 10-fold less than that of cocaine. The hydroxymethane, acetate, amide, benzyl ester, oxidazole, and ethane derivatives of 3 exhibited decreased binding while the vinyl, phenyl, and ethyl esters showed a moderate increase in binding affinity. Only the isopropyl derivative 8 exhibited a 2-fold increase in binding affinity compared with 4'-iodococaine (3). Hydroxylation of 8 at the 2'-position gave 14 which enhanced not only the binding potency at the DAT by another 2-fold but also the selectivity at the DAT over the norepinephrine and serotonin transporters. Compound 14 failed to stimulate locomotor activity in C57BL/6J mice over a wide dose range and blocked cocaine-induced locomotor stimulant action.

New method for measuring myocardial blood flow by high resolution scintigraphy in the excised dog heart.

The standard method for measuring myocardial blood flow (MBF) with radioactive microspheres requires processing of selected tissue samples usually from the excised heart, and consequent loss of exact relation to myocardial morphology. A computer-based image processing method was developed by using [99mTc]microspheres (mean particle size 20 microns) for quantitative analysis of MBF in 25 dogs. A computer-controlled gamma camera was used to obtain the images of radioactive microsphere distribution in transaxial slices of the ex vivo heart. Any portion of these slice images could be quantitated by using a computer program based on modification of the formula for determining MBF by the standard microsphere method. Regional myocardial perfusion calculated by this technique correlated well with values obtained with reference microspheres (r = 0.96) over a broad range of MBF. The results show that our new method, accurately and with high resolution, delineated zones of differing MBF and confirmed the increase of MBF in surviving myocardium with healing.

A new and superior adrenal scanning agent, NP-59.

The first synthesis of 131I-19-iodocholesterol had a 10-25% radiochemical impurity that was not iodide ion. This impurity has been identified as 6beta-131I-iodomethyl-19-nor cholest 5(10)-en-3beta-ol (NP-59) and has been synthesized. Tissue distribution studies with 131I-NP-59 in rats and dogs revealed a higher adrenal uptake and adrenal-to-tissue ratios compared to 131I-19-iodocholesterol, probably less in vivo deiodination, and superior adrenal images. A high uptake was seen in the adrenal medulla in addition to that in the cortex. Iodine-131-NP-59 is being evaluated for the early detection of adrenal-cortical disorders and as a potential scanning agent for detecting structural abnormalities of the adrenal medulla.

Thymic gallium-67 localization in pediatric patients on chemotherapy: concise communication.

Localization of Ga-67 in the thymus has been reported to occur in children. In our control group of 87 patients, 15% of children under 5 yr and 11% of children over 5 yr demonstrated thymic localization. In contrast, in our study group of seven children with acute lymphocytic leukemia or malignant lymphoma, lymphocytic diffuse, treated on a modified non-Hodgkin's lymphoma protocol, Sloan-Kettering LSA2-L2, thymic localization occurred during treatment in five of the seven. We conclude that increased thymic gallium localization in children under chemotherapy for a known malignancy may reflect increased activity of thymic medullary epithelial cells and regeneration of thymic lymphocytes during recovery form involution induced by certain chemotherapeutic agents.

Selenium-75-19-selenocholesterol-a new adrenal scanning agent with high concentration in the adrenal medulla.

A tissue distribution study with 75Se-19-selenocholesterol in rats, rabbits, and dogs showed high adrenal concentrations and good adrenal images. In the dog, higher concentrations were obtained in the adrenal medulla than in the cortex at Days 1 and 7 after dosing. Extraction and thin-layer chromatography of the adrenal lipid in dogs given this compound showed that 75Se in the adrenal is still attached to the steroid moiety. A reduction in production costs is expected from its longer shelf life. Selenium-75-19-selenocholesterol is being evaluated in humans not only for routine use as a adrenal cortex scanning agent, but also for the detection of pheochromocytomas and other sympathetic tissue tumors, especially neuroblastomas.

Inherited, selective hyporesponsiveness to the analgesic action of nicotine in mice.

The acute dose-dependent analgesic activity of nicotine, as measured by the tail-flick assay, differed significantly between CD-1 and CF-1 outbred strains of mice. Differing responsiveness to the tail-flick stimulus did not explain this pharmacological effect. The inherent analgesic hyporesponsiveness of CF-1 mice was pharmacologically selective. Xilocaine and morphine produced an analgesic response of large magnitude in CF-1 mice. Reduced efficacy of nicotine in the CF-1 analgesia assay was not observed in its action on locomotor activity or in the induction of seizures and lethality. These findings have practical significance in identifying the importance of genotype in choice of strain for preclinical pharmacological studies of nicotine-induced analgesia and indicate that genetic analysis may provide a valuable tool for investigating the mechanism underlying the analgesic action of nicotine.

Inherited, selective hypoanalgesic response to cytisine in the tail-flick test in CF-1 mice.

This study extends the pharmacological characterization of the genotype- dependent difference in analgesic responsiveness to neuronal nicotinic agonists between CD-1 and CF-1 strains of mice. Acute analgesic potency of cytisine measured by the tail-flick assay differed by > 3200-fold between CD-1 and CF-1 outbred strains of mice. Analgesic non-responsiveness of the CF-1 strain was pharmacologically selective. Morphine produced a dose-dependent analgesic response of similar magnitude in both strains. Other pharmacological actions of cytisine, including inhibition of locomotor activity, induction of seizures and lethality, did not differ between these strains. Hyporesponsiveness to the analgesic action of both nicotine and cytisine was observed in two different CF-1 sublines. Biodistribution of [3H]cytisine in blood did not differ between the CF-1 and CD-1 strains. These pharmacological characteristics indicate that the CD-1-CF-1 strain pair provides a useful pharmacogenetic tool for investigating the mechanistic bases of analgesia induced by nicotinic cholinergic agonists.

Selective behavioral alterations on addition of a 4'-phenyl group to cocaine.

We synthesized a cocaine analog in which a phenyl group was added at the para-position of the benzene ring of cocaine. This substitution caused a modest reduction (four-fold compared with cocaine) in binding potency for the primate (Papio) dopamine transporter as judged by displacement of [3H]WIN 35,428 binding from caudate/putamen membranes. Behavioral effects of this structural modification in the mouse were complex and selective, comprising absence of stimulation of locomotor activity, enhanced inhibition of locomotion and reduced lethal potency. Convulsant potency was unaltered. Substituents at the 4'-position of cocaine are important in its actions. Simple changes in the chemical structure of this drug may produce complex and selective changes in its neurochemical and behavioral actions.

2'-Substitution of cocaine selectively enhances dopamine and norepinephrine transporter binding.

Few studies have characterized the effect of substituents at the 2'-position of cocaine on transporter binding potency and selectivity. We synthesized 2'-OH-, 2'-F- and 2'-acetoxy-cocaines and compared their binding potencies for rat dopamine, norepinephrine and 5-hydroxytryptamine transporters to cocaine, 3'-OH-, 4'-OH-, 2'-OH,4'-I-cocaine derivatives, and to the transporter selective ligands WIN 35,428, nisoxetine and paroxetine. Unlike most substitutions, 2'-OH- and 2'-acetoxy-groups increased cocaine's binding potency for the dopamine transporter (10- and 4-fold, respectively). These substituents also enhanced binding to the norepinephrine transporter (52- and 35-fold, respectively) but had less effect on 5-hydroxytryptamine transporter binding. 2'-Hydroxylation also enhanced binding of 4'-I cocaine, an analog with low DA binding potency. The ability of 2'-substituents to substantially increase cocaine binding potency and to alter selectivity for brain transporters indicates the potential importance of the 2'-position in transporter binding.

Retinal detachment after strabismus surgery.

Four nonmyopic eyes in three patients developed retinal detachment after strabismus surgery. Certain features common in all four eyes included the presence of a chorioretinal scar corresponding in location to the muscle operated on, proliferating fibrous tissue adjacent to the scar, and varying degrees of vitreous hemorrhage. These findings were similar to those in retinal detachments after perforation of the eye by foreign bodies. Penetration of the globe by the needle during muscle surgery was considered the etiologic factor. The use of spatula needles to prevent piercing of the globe is suggested, and in case such accident is suspected, diathermy or cryoapplication over the perforation site is advised.

First-pass studies of acute lung injury.

Mild hydrochloric acid was introduced to a caudal lung section in each of eight dogs to induce injury. Transits of 99mTc-labeled red blood cells (RBC) and [123I]iodoantipyrine (IAP) injected intravenously were recorded by a scintillation camera. Lungs and blood samples were analyzed post-mortem. Peak-to-equilibrium ratios (P/E) of RBC time-activity curves were computed to be 3.83 +/- 0.54 for the control lung, 2.58 +/- 0.55 for the injured lung and 2.23 +/- 0.58 for the injured caudal section. For IAP, the respective results were 3.78 +/- 0.29, 2.02 +/- 0.18 and 1.77 +/- 0.17. The decrease of P/E in injured areas was attributed to reduced blood flow. Using mean transit times of the tracers, we computed extravascular lung water per unit blood volume to be 0.35 +/- 0.18 for the control lungs and an increased value of 0.68 +/- 0.24 for the injured lungs. These results displayed sensitivity to injury, but were gross underestimates relative to the corresponding values of 2.04 +/- 0.54 and 4.56 +/- 1.85 in post-mortem analyses.

Tissue distribution of 3H-terbutaline in rabbits.

Terbutaline is a widely used, selective beta 2-adrenergic agonist whose penetration into brain has not been demonstrated in laboratory animals. Although its tissue uptake has been reported in some animals, no uptake into brain has been demonstrated. A single dose of 20 microCi of 3H-terbutaline along with 10 mg/kg of unlabeled terbutaline was injected into a rabbit marginal ear vein. The distribution of 3H-terbutaline in several tissues was determined 0.5, 1, 3, or 6 hr later. Radioactivity in the brain was well-maintained over the 6 hr observation period. In most tissues, radioactivity peaked in less than 1 hr, then declined. Radioactivity in the urine was high at all time periods and was highest at 3 hr. Thus, terbutaline or a metabolite(s) does cross the blood-brain barrier in rabbits, and the radioactivity in the rabbit brain does not decrease during the 6 hours following terbutaline injection.

Estrogenic and antiestrogenic activity of novel selenosteroids.

An assay for estrogenic and antiestrogenic activity of seven selenoestrogens has been carried out in immature female rats. The estrogenic activity was compared to the in vitro binding affinity data. The study reveals that introduction of selenium substituents on C-16 or C-17 of the steroid nucleus produced a marked reduction in the estrogenic activity. The selenium analogues of ethynylestradiol produced the highest estrogenic activity. None of the compounds produced antiestrogenic activity.

Kit preparation of radioiodinated o-iodohippuran.

The purpose of this study ws to evaluate a kit preparation for radioiodinated o-iodohippuran (I). All ingredients, excluding the radionuclide, were packaged in a ready-to-use kit for easy, quick formulation. Electrophoresis was utilized to evaluate the radiochemical purity of the labeled product and indicated that the radiolabeling technique provided a product with greater than 95% radiochemical purity. Biodistribution studies in rats and rabbits provided an indication of the tissue distribution and localization of the radiopharmaceutical. Computer-generated renogram curves plotted from gamma-camera images of rabbits showed the equivalency of the 131I-labeled I and 123I-labeled I to the commercially available radiopharmaceutical.

Lymphedema secondary to filariasis.

A 1-year-old immunodeficient boy developed brawny edema of the left foot. Lymphoscintigraphy revealed no evidence of left inguinal activity following pedal injection of Tc-99m-Sn phosphate. Over the next two months, the patient developed lymphedema on the right and repeat scintigraphy demonstrated no movement of isotope from the dorsum of either foot. Subsequent studies identified microfilaria in a nocturnal blood smear, which were thought to represent Brugia beaveri acquired by mosquito transmission in Oklahoma.

An evaluation of diagnostic techniques utilized in the initial workup of pediatric patients with acute lymphocytic leukemia.

The records of 32 pediatric patients with acute lymphocytic leukemia (ALL) were reviewed to evaluate the role of various diagnostic techniques used to assess the extent of extramedullary disease. Our findings indicate that adequate screening for hepatosplenomegaly is obtained by clinical assessment and for bone and renal involvement by bone scintigraphy including concomitant renal imaging. We recommend that radiographs be restricted to scintigraphically abnormal areas and/or sites of bone pain. Liver-spleen scintigraphy, gallium studies, intravenous pyelography, and ultrasound studies of the abdomen and pelvis should be utilized only to answer specific clinical questions. Evaluation in this manner reduces both radiation exposure and patient expense, while it adequately defines the extent of disease in these organs.