Arnold M. Friedman

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.

Production of 75Br via the 78Kr (d,nα)75Br reaction

The production of 75Br by the 78Kr(d,nα)75Br reaction using a 21.5 MeV deuteron beam was investigated. With our 78Kr gas target, the production yield was found to be 5.9 ± 0.9 mCi/μA at saturation. The major impurities in the 75Br product were 76Br and 77Br which amounted to about 6 and 2.5%, respectively, at EOB. Sufficient amounts of 75Br could easily be prepared by this method for use in chemistry and animal experiments but deuteron energies >20 MeV are required.

The synthesis of non-steroidal estrogen receptor binding compounds labeled with 80mBr.

Estrogen receptor (ER) binding radiopharmaceuticals have potential for use in the diagnosis and treatment of cancers of the female reproductive system. Two triphenylethylene derivatives based on the structure of hydroxytamoxifen 4, a high ER binding metabolite of tamoxifen 5, have been prepared: 1-(4-dimethylaminoethoxy)phenyl]-1-(4-hydroxy)phenyl-2-bromo-2-phenyl ethylene 2 and 1,1-bis (p-hydroxyphenyl)-2-bromo-2-phenylethylene 3. Both 2 and 3 bind strongly to the ER. Compound 3 has been labeled in modest yield by direct bromination with 80mBr, which was produced by the 83Kr (d,n alpha) reaction. Radiolabeled 22, a dimethoxy precursor of 3, has been prepared in yields ranging between 40 and 60% by a bromination destannylation reaction.

Radiobrominated spiroperidol for the study of dopamine D2 receptors

Some neuropsychiatric disorders have been suggested to be related to the CNS dopaminergic system. In order to probe this neurotransmitter system, radiobrominated spiroperidol, a potent dopamine (DA) D2-receptor antagonist, was developed. This review deals with the routine synthesis of [75, 76, or 77Br]-p-bromospiroperidol (BrSP), its validation as a radiopharmaceutical directed to DA D2 receptors, and the imaging studies which have been done using this radioligand with either single photon tomography (SPECT) or positron tomography (PET). [*Br]BrSP will be compared to other D2 ligands currently available. The present state and future direction of DA receptor research, in particular, the quantitative aspects, will be discussed.

Pulmonary function and 81mKr scans in obstructive pulmonary disease

Abstract Pulmonary ventilation in 13 normal subjects and in 18 patients with known chronic obstructive pulmonary disease (COPD) has been characterized with two modalities. Comparison consisted of correlating standard pulmonary function tests (PFT) and scintigraphic images of the lungs under steady state conditions during tidal respiration of krypton-81m. The lung scintigram was evaluated by inspection and a computer generated histogram in which the ratio of low level and high level ventilation of the lung was determined. Pulmonary function tests were the basis for verifying normality in 13 subjects. Scintigraphic imaging and histogram analysis in 18 patients with COPD produced two false negative results by each method. The combined scintigraphic histogram results correctly defined 13 of 13 normal subjects. The two scintigraphic methods differentiated normal subjects from patients with known COPD with a high level of comparability to PFT.

Production of no carrier added 80mBr for investigation of Auger electron toxicity

80mBr (half-life = 4.43 h) is an Auger electron emitting nuclide with convenient properties for investigating Auger electron cytotoxicity and with potential for labeling in vivo radiotherapeutic agents. We have investigated three cyclotron target systems capable of generating 80mBr of sufficiently high specific radioactivity (no carrier added) for biomedical experiments. A 83Kr gas target irradiated with 21.5 MeV deuterons made 80mBr at a production yield of 1.6 +/- 0.2 mCi/muAh at saturation. A five-fold increase in 80mBr yield was obtained from 15 MeV proton irradiation of thin elemental Se enriched in 80Se targets although technical improvements are expected to further raise this production yield. This route is therefore superior for current medical cyclotrons. Irradiation of a reusable 80Se copper selenide target also yielded multi-millicurie amounts of 80mBr, and recovery of radiobromine by dry distillation is faster and more convenient than in the elemental Se target, but an optimum copper selenide target for 80mBr production has not yet been built.

Migration of uranium process wastes from the uranium-233--thorium-232 cycle

With the advent of fuel loadings of uranium-233 in the Shippingport Reactor, it has become important to understand the migratory behavior of uranium. The purpose of this study is the determination of the parameters influencing the migration of uranium(VI), the most likely chemical form of uranium to be mobilized from a repository. Samples of rhyolite tuff were used to measure the absorption coefficients of solutions of uranium (VI) in ground waters. In addition, columns of tuff were used to measure the elution behavior of uranium (VI) at various conditions of pH, uranium (VI) concentration, and flow saturation. These results indicate that there are several elution peaks with values of Kd between 35 and 120. This behavior is not the same as that of Plutonium(VI) on tuff; and the experimental results to date have not revealed the reason for this difference. Values of Kd in this range imply that geological containment would be difficult in strata of this type. It may be possible to find more retentive strata than tuff. Rocks containing reducing components are the most likely candidates and further investigation is urgently needed if the uranium-233-thorium cycle is to be widely used.

Studies of nuclear waste migration in geologic media. Annual report, October 1978-September 1979

Annual report of the Argonne National Laboratory Chemical Engineering Division regarding studies of nuclear waste migration in geologic media. This report discusses research regarding nuclide migration by fluid flow in rock.