Positron emission tomography with fluorine-18-deoxyglucose in the detection and staging of breast cancer.

BACKGROUND: An increasing number of patients with breast cancer is being treated with preoperative chemotherapy. Evaluation of treatment response may be facilitated by positron emission tomography (PET) with 18F-fluoro-2-deoxy-D-glucose (FDG). This noninvasive technique may allow prediction of the chemotherapy outcome in an early phase of the treatment. METHODS: Prerequisites for treatment monitoring with PET are good FDG uptake in the tumor, high specificity, and a reliable quantification technique. These factors were studied in 20 patients with primary breast cancer, lymph node metastases, benign breast lesions, a combination of these abnormalities, or no abnormality. RESULTS: In 10 of 11 patients with primary breast cancer, the tumor was visualized. The median tumor-to-normal-tissue-uptake ratio was 4.9. In all five patients with increased uptake in the lymph node basin, pathologic proof of metastatic cancer was found. Of the patients with benign or no disease of the breast, slightly increased uptake was seen in one patient with fibrocystic disease. CONCLUSION: It is concluded that PET with FDG can be used for breast cancer imaging and staging.

Halogenated analogues of tamoxifen: synthesis, receptor assay, and inhibition of MCF7 cells.

This study was conducted to develop a ligand for imaging estrogen-receptor-positive breast tumors by positron emission tomography or single photon emission computed tomography. We synthesized fluoro and iodo analogues of tamoxifen, and these halogenated analogues produced greater affinity for binding to the receptor than tamoxifen. Values of the inhibition affinity constants were as follows: tamoxifen, 15,000 nM; fluoromethyl-N,N-diethyltamoxifen, 2500 nM for the cis isomer and 500 nM for the trans isomer; and iodomethyl-N,N-diethyltamoxifen, 1500 nM for the cis isomer and 1000 nM for the trans isomer. In studies of human MCF7 breast tumor cell growth, concentrations that inhibited tumor growth in 50% of the cases were as follows: tamoxifen, 11 microM; fluoromethyl-N,N-diethyltamoxifen, 4.5 and 11.8 microM for the cis and trans isomers, respectively; and iodomethyl-N,N-diethyltamoxifen, 2.4 and 6.3 microM for the cis and trans isomers, respectively. These studies suggest that both fluoro and iodo analogues of tamoxifen may be useful diagnostic compounds for predicting the response of estrogen-receptor-positive breast tumors to tamoxifen analogues used in chemotherapy.

Differentiation of residual or recurrent tumors from post-treatment changes with F-18 FDG PET.

Positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) was used to differentiate recurrent or residual malignant disease from the effects of cancer treatment. Transaxial images were obtained after injection of 5-10 mCi (185-370 MBq) of F-18 FDG in 68 patients (including 33 with brain tumors) whose posttreatment computed tomographic (CT) or magnetic resonance (MR) imaging findings had been suggestive of malignant disease. PET findings were correlated with surgical results in 18 patients and with the outcomes of CT, MR imaging, clinical, and laboratory 9-month follow-up studies in 50 patients. There was good agreement between F-18 FDG uptake and presence or absence of malignant disease except in four cases of brain tumors in which histologic findings could not be correlated with biologic behavior. The putative sensitivity and specificity in the 33 cases of brain tumors were 80% and 94%, respectively. The authors conclude that PET with F-18 FDG is useful in detection of previously treated metabolically active tumors but is limited in diagnosis of recurrent microscopic or metabolically inactive tumors.

Synthesis and in vitro receptor binding studies of fluorotamoxifen analogues.

We describe the synthesis of new fluorotamoxifen analogues with the fluorine atom positioned on the end of the aliphatic chain of tamoxifen. The binding of fluorotamoxifens to cytosol estrogen receptors of rat uteri was determined with [3H]estradiol (5 nM). The fluorotamoxifens had similar or superior binding affinities compared with tamoxifen. The IC50 value was as follows: tamoxifen, 5 x 10(-7) M; fluorotamoxifen (VII), 5 x 10(-7) M; N,N-diethylfluorotamoxifen (IV)-cis, 1 x 10(-6) M, and trans, 2 x 10(-7) M; and (cis) fluoromethyl-N,N-diethyltamoxifen (VI) 1 x 10(-7) M. Therefore, the fluorinated tamoxifens have potential use in imaging estrogen receptors by PET.

Reusable gels for germanium-68 sources.

Two water-soluble gels, gelatin and Carbowax, were mixed with radioactive 68Ge solutions and evaluated for their use as long-lived (half-life, 280 days) radioactive sources. These gels melt at 40-50 degrees C and solidify at room temperature. The amount of 68Ge mixed with them can be increased or decreased as needed, eliminating waste of 68Ge. These gel sources also may replace short-lived 68Ga (half-life 68 min) as attenuation correction sources in positron emission tomography (PET) and reduce frequency of source preparation, thus reducing exposure of PET operators to radiation.

Radionuclide production and partial radiochemical characterization following fast neutron irradiation of mouse spleens.

When radiotherapy patients are irradiated with fast neutron beams (energies greater than 20 MeV), positron emitting radionuclides (15O, 13N, 11C) are created in their tissues. Capillary blood flow can be determined in the irradiated tissue by measuring the washout of the 15O. The chemical form of these positron emitting nuclides is important when assumptions about their transport in the development of a blood flow model are being made. In the present work, normal mouse spleen tissue was used as a model system for these studies. The mouse spleen was activated by whole mouse irradiation using the M.D. Anderson Hospital neutron beam produced by 42 MeV protons impinging on a beryllium target. Results of cellular studies and large molecule precipitation measurements (1) show that at least 65% of 15O created in situ in mouse spleen is capable of being transported out of the spleen by the blood supply, (2) suggest that 13N may be 100% biologically mobile, and (3) indicate that 11C appears to be evenly divided between a population associated with small biologically mobile molecules and a population associated with larger, biologically trapped or immobile molecules.

Distribution of 13N in rat tissues following intravenous administration of nitroso-labeled BCNU.

The concentrations of label in 16 major organs and tissues of pentobarbital-sedated normal male rats were measured at six time points ranging from 0.2 to 50 min after IV injection of the antitumor drug BCNU labeled in the nitroso position with cyclotron-produced nitrogen-13. Initial (12-s) concentrations in the lungs, kidneys, and heart were 41, 13, and 11 times the whole-body average, respectively. Time for clearance of the first 50% of the injected dose from the circulation was of the order of several seconds. Estimated first-pass extractions of 70% or more were noted in the heart, kidneys, brain, stomach, small intestine, muscle, fat, and bone. Washout of label from the heart and lungs was quite rapid, removing most of the initially extracted 13N from these organs by 2 min after injection. Label concentrations in the kidneys exceeded those in all other tissues studied between 2 and 50 min. Secondary accumulations of 13N were observed in muscle, skin, liver, small intestine, and fat. Label concentrations in a number of tissues closely paralleled the steadily decreasing concentration in blood for various intervals between 5 and 50 min. The results suggest that the toxic insult to lung tissue from IV administered BCNU is effected in a period of several minutes. They also suggest that intra-arterial administration of the drug would significantly raise the target/non-target dose ratio and lower the incidence of pulmonary toxicity.

Synthesis of [2-11C]5,5-dimethyl-2,4-oxazolidinedione for studies with positron tomography.

We have developed a method for the synthesis of [2-11C]5,5-dimethyl-2,4-oxazolidinedione ([2-11C]DMO) for use with positron emission tomography to measure regional tissue pH in vivo in man. [2-11C]Dimethyl carbonate (DMC) was prepared from [C-11]phosgene and excess of sodium methoxide in methanol containing dimethyl carbonate as added carrier. The [2-11C]DMC solution was then reacted with 2-hydroxyisobutyramide at 150 degrees C for 10 min to yield, after HPLC separation, [2-11C]DMO with a radiochemical yield of 20-56%. Chemical yields were 78-92%, and specific activity ranged as high as 830 mCi/millimol.

Tissue distribution studies of [18F]haloperidol, [18F]-beta-(4-fluorobenzoyl)propionic acid, and [82Br]bromperidol by external scintigraphy.

Tissue distribution studies of [18F]haloperidol and [82Br]bromperidol, two potent neuroleptic drugs, were performed in rats by serial sacrifice. The usefulness of external scintigraphy in obtaining tissue distribution data in large animals is demonstrated by the tissue distribution of [18F]haloperidol in rhesus monkeys. Both serial sacrifice and external scintigraphic studies demonstrated that uptake of the two drugs after intravenous administration into their target organ, the brain, was very fast and that the ratio of brain to blood levels was high throughout the 2-hr observation. Bromperidol appeared to reach peak brain levels faster than its chloro analog, haloperidol. Both bromperidol and haloperidol concentrated overwhelmingly in the rat lung. Haloperidol also showed a high affinity for the monkey lung. The disposition pattern in rats of [18F]-beta-(4-fluorobenzoyl)propionic acid, an apparent intermediate in butyrophenone metabolism, was entirely different from that of the parent drugs. This metabolite did not concentrate in the rat brain.

Production of 7.6-minute potassium-38 for medical use.

A method is described for generating 20--30 mCi of 7.6-min potassium-38 by means of a small cyclotron. Sodium chloride is mounted on a water-cooled tantalum plate, by evaporation from an aqueous solution. It is bombarded with 14.7 MeV helium-4 ions, at 50 microA. The K-38 is produced free of other radionuclides. For intravenous injection the bombarded NaCl is dissolved in sufficient pyrogen-free water to make an isotonic saline solution, which then is sterilized by filtration. Other methods of production investigated were the bombardment of: carbon tetrachloride with He-4 ions; calcium oxide with 7.8-MeV deuterons; and potassium chloride with 23-MeV He-3 ions. These gave products that were unsuitable for clinical applications. Chiefly because of the short half-life of K-38, the whole-body radiation exposure is estimated to be only about 12 mrad/mCi, and exposures to the heart and kidneys are approximately ten times greater.

In vivo distribution of carbon-11 phenytoin and its major metabolite, and their use in scintigraphic imaging.

Curie quantities (0.3--1.5 Ci) of H11CN were used in the synthesis of C-11-tagged phenytoin (C-11.DPH) and 5-(p-hydroxyphenyl)-5-phenylhydantoin (C-11.HPPH), using a modified Bücherer-Bergs reaction. The H11CN was produced from a mixture of 95% nitrogen and 5% hydrogen by a 45-min bombardment with 10-MeV protons at 10 muA. Following i.v. infusions of C-11 DPH (13.7 mg/kg at a rate of 29 mg/min) into the left femoral vein of Rhesus monkeys, DPH shows persistent concentration in the brain and liver fields. Extravascular administration shows significant retention at the site of administration. Intravenous bolus injection of [11C]-HPPH into a Rhesus monkey, at a dose of 6.4 mg/kg, resulted in localization of this compound in the liver, gallbladder, urinary bladder, and intestinal fields. Loss of activity from the liver region, with appearance of this activity in the intestinal field, suggests that [11C]-HPPH is secreted into the intestine via the bile. Further investigation is needed to study the potential of [11C]-DPH as a brain-scanning agent and [11C]-HPPH as a possible cholescintigraphic agent.