An improvement of 11C acetate synthesis--non-radioactive contaminants by irradiation-induced species emanating from the 11C carbon dioxide production target.

An existing procedure for [11C]acetate synthesis, consisting of a reaction of methylmagnesium chloride and [11C]carbon dioxide in tetrahydrofuran, hydrolysis and ion-exchange purification on small columns, has been improved. The use of less Grignard reagent and application of commercial cartridges instead of home made ones led to an increase of the overall yield from 60-65% to over 80%. Malfunction in pure nitrogen targets for 11C production may lead to unexpected contaminants. It is recommended to incorporate in the target outlet line a trap for removal of nitrogen oxides.

[11C]Formaldehyde revisited: considerable concurrent [11C]formic acid formation in the low-temperature conversion of.

The reduction of [11C]carbon dioxide with lithium aluminium hydride in diethyl ether at temperatures ranging from -56 degrees C to 19 degrees C was studied. In contrast to what others have reported, considerable amounts of [11C]formic acid were found at all studied temperatures.

Synthesis of [11C]RPR-72840A and its evaluation as a radioligand for the serotonin reuptake site in positron emission tomography.

RPR-72840A, an inhibitor of serotonin reuptake, was labelled with carbon-11. The synthesis of the nonradioactive precursor, which exhibited some unexpected chemistry, and its reaction with [11C]phosgene affording [11C]RPR-72840A are described. Biodistribution studies in rats and PET studies in baboons were conducted to evaluate [11C]RPR-72840A as a tracer for PET imaging of the serotonin reuptake system.

Deoxyglucose uptake in the ferret auditory cortex.

Histological methods and 2-deoxyglucose autoradiography were used in an attempt at finding distinguishing characteristics that would permit the clear definition of different auditory areas on the ectosylvian gyrus. This region was studied in both coronal and flattened tangential sections. In tangential sections a crescent-shaped region of high deoxyglucose uptake was identified. The centre of this crescent was in the position of the primary auditory area on the middle ectosylvian gyrus. The ventro-anterior arm of the crescent was on the surface of the anterior ectosylvian gyrus and the ventro-posterior arm on the posterior ectosylvian gyrus. All three parts of the crescent appear to have an auditory function, because ablating the inferior colliculus or inserting a contralateral earplug reduced their deoxyglucose uptake. This was shown by using two separately distinguishable forms of 2-deoxyglucose, incorporating the 18F and 14C isotopes. In addition, another area of high deoxyglucose activity was identified in the ventral wall of the suprasylvian sulcus, which seems to correspond to the anterior auditory field. These four areas with high deoxyglucose uptake also have high levels of succinate dehydrogenase activity and moderately high densities of myelinated fibres. Succinate dehydrogenase histochemistry provides a simple method for identifying auditory cortical areas and should be of use in future physiological studies. These results provide evidence that the ferret has four separate auditory areas with relatively high metabolic and functional activity.

Limbic dysfunction in schizophrenia and mania. A study using 18F-labelled fluorodeoxyglucose and positron emission tomography.

BACKGROUND: Diagnostic classes (derived from CATEGO) can be correlated with regional brain metabolism in patients with major psychiatric disorders. METHOD: Seventeen patients with schizophrenia, 15 with mania, 10 with depression and 10 healthy Volunteers were examined with positron emission tomography (PET) and 18F-labelled fluorodeoxyglucose, as a marker for glucose metabolism. The number of possible comparisons of regions of interest was reduced by principal-components analysis, and differences in factor scores were determined between diagnostic groups. RESULTS: Four independent factors, representing distributed brain systems, emerged: an anterior-posterior (1), a left-right temporal (2), a temporofrontal (3), and a mediofrontal (4) system, of which (1), (2) and (3) were abnormal in schizophrenia, (1) and (2) in mania, and (1) in depression. CONCLUSIONS: Abnormal patterns of metabolism could be detected, in decreasing order, in schizophrenia, mania and depression. Some of these abnormalities are likely to be due to medication, but others will be associated with structural or functional abnormalities of the frontolimbic system in the diagnostic groups.

Synthesis and in vivo distribution of no-carrier-added N(omega)-Nitro-L-arginine [11C]methyl ester, a nitric oxide synthase inhibitor.

N(omega)-nitro-L-arginine methyl ester (L-NAME) was labelled with carbon-11 as a potential PET tracer for NO synthase. N(alpha)-t-butoxycarbonyl-N(omega)-nitro-L-arginine was reacted with [11C]diazomethane. After deprotection with trifluoroacetic acid the formed [11C]L-NAME was purified using HPLC. Biodistribution studies in rats and PET studies in monkeys and dogs showed no correlation between radioactivity distribution and NO synthase localization in brain and heart. Substantial amounts of [11C]methanol were detected in dog plasma shortly after injection. These findings preclude the use of [11C]L-NAME as a PET tracer.

In vivo metabolites of N omega-nitro-L-arginine methyl ester: methanol and N omega-nitro-L-arginine.

N omega-nitro-L-arginine methyl ester (L-NAME) is commonly used as a selective inhibitor for in vivo studies of brain nitric oxide (NO) synthase. We aimed to study the fate of N omega-nitro-L-arginine [11C]methyl ester ([11C]L-NAME) using positron emission tomography in monkey and high performance liquid chromatography methods in dogs and rats. We found that [11C]L-NAME was rapidly (t1/2 = 2 min) metabolized into N omega-nitro-L-arginine (L-NA) and [11C]methanol which both had a slow rate of elimination. Although, in vivo, L-NAME administration leads to long-lasting NO synthase inhibition by L-NA, methanol which is a potent neurotoxin in primate may produce detrimental effects unrelated to NO synthase inhibition.

Measurement of blood flow in tibial fracture patients using positron emission tomography.

The quantification of local bone blood flow in man has not previously been possible, despite its importance in the study of normal and pathological bone. We report the use of positron emission tomography, using 15O-labelled water, to measure bone blood flow in patients with closed unilateral fractures of the tibia. We compared fractured and unfractured limbs; alterations in blood flow paralleled those found in animal models. There was increased tibial blood flow at the fracture site as early as 24 hours after fracture, reaching up to 14 times that in the normal limb at two weeks. Blood flow increase was less in displaced than in undisplaced fractures. The muscle to bone ratios of blood flow were similar to those in previous animal work using other techniques. Positron emission tomography will allow study of human bone blood flow in vivo in a wide variety of pathological conditions.

Pattern of 2-deoxy-2-[18F]-fluro-D-glucose accumulation in liver tumours: primary, metastatic and after chemotherapy.

Eight patients with liver metastases from adenocarcinoma of the colon or rectum, two with suspected hepatic metastases and one with primary hepatoma were studied with 2-deoxy-2-[18F]-fluro-D-glucose (18F-FDG) using positron emission tomography (PET). In five of the patients with metastatic tumour a second examination was performed four weeks after treatment with recombinant interleukin-2 (rIL2) and fluorouracil (5FU). In all tumours (one primary and eight metastatic) the radioactivity was seen to accumulate in a rim around each tumour with a large central area showing no uptake. In the five cases imaged after treatment with rIL2, the appearance of the tumour uptake was the same as before treatment. In the two cases of suspected but not proven metastases, no abnormal accumulation of 18F-FDG was seen.

Regional cerebral blood flow imaging: a quantitative comparison of technetium-99m-HMPAO SPECT with C15O2 PET.

The aim of this study was to compare technetium-99m-hexamethylpropyleneamineoxime (99mTc-HMPAO) single-photon emission computed tomography (SPECT) with regional cerebral blood flow (rCBF) imaging using positron emission tomography (PET). As investigation of dementia is likely to be one of the main uses of routine rCBF imaging, 18 demented patients were imaged with both techniques. The PET data were compared quantitatively with three versions of the SPECT data. These were, first, data normalized to the SPECT cerebellar uptake, second, data linearly corrected using the PET cerebellar value and, finally, data Lassen corrected for washout from the high flow areas. Both the linearly-corrected (r = 0.81) and the Lassen-corrected (r = 0.79) HMPAO SPECT data showed good correlation with the PET rCBF data. The relationship between the normalized HMPAO SPECT data and the PET data was nonlinear. It is not yet possible to obtain rCBF values in absolute units from HMPAO SPECT without knowledge of the true rCBF in one reference region for each patient.

Biodistribution and scintigraphy of 11C-toremifene in rats bearing DMBA-induced mammary carcinoma.

A new antioestrogenic antitumour compound toremifene was labeled with 11C or 3H. The tissue distribution and tumour uptake of the compounds in DMBA induced breast tumour bearing rats was investigated. 11C-toremifene was localized by gamma camera scintigraphy and tissue counting. 3H-Toremifene was determined by liquid scintillation counting after oxidizing the tissue samples. Toremifene was distributed to several tissues due to the lipophilicity and was not taken up specifically by the tumours to any great extent. However, the radioactivity of the tumours increased as a function of time although it declined e.g. in the liver. The accumulation to the tumour was a slow process and cannot be followed up reliably by such short half-life radionuclides as 11C. The tumour uptake properties of toremifene resemble those of tamoxifen and several other oestrogen receptor binding compounds. These substances have limited use in diagnosing and imaging oestrogen receptor rich breast tumours in man.

Comparative double-tracer whole-body autoradiography: uptake of 11C-, 18F- and 3H-labeled compounds in rat tumors.

The uptake of various labeled compounds by tumors was studied by double-tracer whole-body autoradiography (DTWBA) in rats. Each animal carried two types of tumors: mammary carcinomas and the Walker 256 carcinosarcomas. The markers used were [18F]- and [3H]fluorodeoxyglucose (glucose utilization), [3H]thymidine (cell proliferation), [11C]methionine (amino acid metabolism) and [11C]- and [3H]toremifene (estrogen-receptor-avid agents). In each experiment, the distribution of a substance labeled with short-lived radionuclide (11C or 18F) was compared with that of another substance labeled with a long-lived nuclide (3H). Quantification was done by combining computerized image analysis of the autoradiograms with liquid scintillation counting of punched tissue pieces obtained from the cryosections. The relationships between the uptakes of the various radiopharmaceuticals were recorded in tumors and normal tissues. The dynamics of [18F]fluorodeoxyglucose and [11C]methionine were determined in tumors and some selected tissues by positron emission tomography (PET). The uptake rate between fluorodeoxyglucose and thymidine in the mammary tumor was five times higher than the ratio in the Walker tumor. The corresponding figure for FDG/methionine was four times. Thymidine, compared with methionine, was twice as efficient. Thus, the mammary tumors were best imaged with FDG or thymidine. The non-steroid antiestrogen toremifene was taken up in very low amounts by these tumors. By DTWBA, experimental tumors may serve as their own control.

Organ and tumor distribution of (18F)-2-fluoro-2-deoxy-D-glucose in fasting and non-fasting rats.

Differences in the uptake of (18F)-2-fluoro-2-deoxy-D-glucose ((18F)FDG) in various normal organs and the Rous sarcoma of fasted and unfasted rats were studied at 5, 15, 30, 60, and 120 minutes after i.v. injection. The uptake of (18F)FDG in the tumor, spleen, and testis increased for 120 minutes, while uptake in the other organs was either level (brain, heart, white fat) or cleared off. The uptake was higher in the tumor than in the normal organs. The fraction of viable tumor tissue as measured morphometrically correlated intraindividually with the uptake of (18F)FDG--an increase of 1% of vital tumor corresponded to a 1.01-fold increase in tumor uptake of (18F)FDG. The nutritional state was of importance for the uptake of (18F)FDG into the heart, testis and brown fat. (18F)FDG is taken quantitatively up by the viable parts of the Rous tumor; this may make it possible to follow the response of treatment in individual tumors also in man with (18F)FDG and positron emission tomography (PET).

Scintigraphy with [18F]2-fluoro-2-deoxy-D-glucose of cancer patients.

Computerized dynamic gamma camera scintigraphy was performed with [18F]2-fluoro-2-deoxy-D-glucose [( 18F]FDG) on 10 patients with different cancers; tumor perfusion was evaluated in four patients with 99mTc-DPD. All tumors were visible in the [18F]FDG scans with tumor-to-tissue image contrast ratios of 1.2-11.7. Tumor perfusion exceeded that of the surrounding normal tissue in three of the four patients studied. Tumor-to-normal tissue [18F]FDG ratios were plotted as a function of the time. Two types of curves emerged: curves showing a linear increase in the ratio and curves showing a constant value for the ratio. These studies show that [18F]FDG can be used for clinical tumor imaging with a gamma camera, and that there appears to be biological differences in tumor uptake of [18F]FDG.

Imaging of canine cancers with 18F-2-fluoro-2-deoxy-D-glucose (FDG) suggests further applications for cancer imaging in man.

18F-2-fluoro-2-deoxy-D-glucose (FDG) is a novel radiopharmaceutical that has gained much interest as a cancer-seeking agent. In this paper two cases of histologically verified canine cancer, an osteosarcoma and a mammary carcinoma, are presented. After an intravenous bolus injection of FDG, accumulation of radioactivity over the neoplastic lesion was followed with a computer-guided specially collimated gamma camera. Ratios of radioactivity between tumour and control areas at 30 min were 2.8 and 2.2 for the osteosarcoma and the mammary carcinoma, respectively. In the osteosarcoma, which was imaged for 3 h, this ratio remained essentially stable. It is reasonable to assume that FDG will be suitable for cancer imaging in man.