Evaluation of technetium-99m exametazime stabilised with cobalt chloride as a blood flow tracer in focal cerebral ischaemia.

A protocol has been devised to effectively extend the limited post-reconstitution shelf life of technetium-99m exametazime as a radiopharmaceutical for imaging cerebral blood flow (CBF) distribution. The potential of 99mTc-exametazime stabilised with cobalt chloride for imaging CBF distribution as late as 4 h after reconstitution has been examined in ischaemic and non-ischaemic tissue in halothane-anaesthetised cats. Focal cerebral ischaemia was produced by permanent middle cerebral artery occlusion. The relationship between 99mTc-exametazime uptake and retention and CBF (assessed with [14C]iodoantipyrine 10 min after first radiopharmaceutical administration) was determined in the same tissue section with double label autoradiography. Over the CBF range 0-80 ml 100 g-1 min-1, the uptake of 99mTc-exametazime (quantitatively and topographically) was linearly related to CBF irrespective of whether the 99mTc-labelled tracer was unstabilised (and administered within 10 min of reconstitution) or was stabilised with cobalt chloride (and administered up to 240 min after reconstitution). For levels of CBF in excess of 80 ml 100 g-1 min-1 the excellent topographical relationship between 99mTc-exametazime distribution and CBF is maintained but quantitatively, 99mTc-exametazime underestimates CBF to a similar degree in animals receiving stabilised and unstabilised 99mTc-exametazime. The presence of the stabiliser, cobalt chloride, extends greatly the period over which 99mTc-exametazime can be used after reconstitution to generate images of CBF distribution in normal and ischaemic cerebral tissue.

A method for stabilising technetium-99m exametazime prepared from a commercial kit.

Technetium-99m exametazime (99mTc-d,l-HMPAO), prepared by the reconstitution of the Ceretec kit, is widely used in the investigation of regional cerebral blood flow. The radiochemical purity specification of not less than 80% lipophilic complex requires that the kit is used within 30 min of reconstitution. In certain circumstances this imposes restrictions on its clinical availability. A number of approaches to extending the 30-min shelf life have been proposed and these are discussed. A method of stabilising the kit by the addition of 200 micrograms cobalt chloride hexahydrate (CoCl2 x 6H2O) in 2 ml of water is described. The addition of this solution can extend the shelf life of the reconstituted kit to at least 5 h post reconstitution.

Technetium-99m-tetrofosmin as a new radiopharmaceutical for myocardial perfusion imaging.

A new cationic complex, [99mTc(tetrofosmin)2O2]+, where tetrofosmin is the ether functionalized diphosphine ligand 1,2-bis[bis(2-ethoxyethyl)phosphino]ethane, has been synthesized and evaluated for potential use in myocardial perfusion imaging. The structure of the complex has been determined by x-ray crystallography of the 99Tc analog. In comparison with previously reported 99mTc complexes of alkyl-phosphines, the tetrofosmin species shows substantially increased clearance from nontarget tissue, especially blood and liver. A freeze-dried kit formulation has been developed. The kit provides a product of high radiochemical purity up to 8 hr after reconstitution at room temperature.

Technetium-99m-1,2-bis[bis(2-ethoxyethyl) phosphino]ethane: human biodistribution, dosimetry and safety of a new myocardial perfusion imaging agent.

A novel 99mTc complex (1,2-bis[bis(2-ethoxyethyl)phosphino] ethane, 99mTc-tetrofosmin) has been developed to replace 201Tl in myocardial perfusion imaging. Biodistribution, safety and dosimetry of 99mTc-tetrofosmin were studied in 12 male volunteers, each at rest and during exercise. Safety parameters measured to 48 hr postinjection revealed no clinically significant long-term drug-related changes. Biodistribution was studied by acquiring whole-body or serial static images up to 48 hr postinjection. Technetium-99m-tetrofosmin shows good heart uptake (1.2%) with retention. Clearance is excellent from blood (< 5% by 10 min), liver (< 4.5% by 60 min) and lung. Sequestration of activity by skeletal muscle is enhanced during exercise. Radiation dosimetry calculations indicate that the effective dose, assuming a 3.5 hr bladder voiding period, is 32.9 x 10(-3) rad/mCi (8.9 x 10(-3) mSv/MBq) at rest and 26.7 x 10(-3) rad/mCi (7.1 x 10(-3) mSv/MBq) after exercise. Technetium-99m-tetrofosmin can produce high quality myocardial images from 5 min to several hours postinjection.

Lipophilic 99mTc-nitride radiopharmaceuticals as potential myocardial imaging agents.

Monocationic 99mTc-nitrido complexes of a variety of diphosphine ligands have been prepared and the in vivo distribution of such cations has been examined in Sprague-Dawley rats. These complexes show initially high myocardial uptake with subsequent wash-out in this animal model. The lack of myocardial retention can be attributed to the facile in vivo reduction of these cations.

99Tcm-labelled meso-HMPAO and glutathione content of human lung tumours.

Levels of reduced glutathione (GSH) are increased in some types of malignant tumours and are known to influence the response to radio- and chemotherapy. In vitro studies suggest a correlation between cellular GSH concentration and retention of the meso form of hexamethyl propyleneamineoxime (HMPAO). This study investigates the relationship between in vivo tissue retention of 99Tcm-labelled HMPAO and GSH concentration in ten patients referred for thoracotomy for possible lung cancer. Retention of 99Tcm-HMPAO was measured using single photon emission computed tomography (SPECT). The tumour and normal lung concentration of reduced glutathione (GSH) was measured in tissue specimens collected peroperatively. Malignancy was confirmed in eight patients. Of seven patients undergoing curative resection for carcinoma, tumour GSH concentration was higher (mean 2.76 mM) than normal lung (mean 1.04 mM). In one neurofibroma, the GSH concentration was 1.80 mM. No correlation was found between 99Tcm meso-HMPAO retention and either the tumour GSH concentration or the tumour:lung GSH ratio. The results from this small series demonstrate that the intracellular GSH concentration of malignant lung tumours is generally higher than that in normal lung but that meso-HMPAO retention could not be used to predict these levels.

Development of a 99Tcm-labelled radiopharmaceutical for cerebral blood flow imaging.

A new radiopharmaceutical, 99Tcm-hexamethylpropyleneamine oxime (99Tcm-HM-PAO) has shown considerable promise for single photon emission tomographic (SPECT) imaging of the brain. In animal biodistribution studies this complex demonstrates good brain uptake with prolonged retention of activity in brain. Further improvement of these properties, resulting in higher brain uptake with very slow washout and fixed regional distribution has been achieved following the isolation of the d,1-diastereoisomer of HM-PAO.

Cerebral uptake and retention of 99Tcm-hexamethylpropyleneamine oxime (99Tcm-HM-PAO).

A new radiopharmaceutical, 99Tcm-hexamethylpropyleneamine oxime (99Tcm-HM-PAO) is described. This agent displays considerable promise for imaging cerebral blood flow. In studies in rats and one human volunteer, 99Tcm-HM-PAO demonstrates good brain uptake, prolonged retention of activity in the brain, and slow regional redistribution. These properties suggest that this new radiopharmaceutical is ideal for single photon emission tomographic (SPECT) imaging of cerebral blood flow.

Urinary pseudouridine/creatinine ratio as an indicator of gastrointestinal cancer.

Urinary pseudouridine/creatinine ratio was determined in 74 patients with gastrointestinal tumours and 34 patients with no known malignant disease. The reproducibility of a single random urine sample was demonstrated. The mean ratio for control patients was 26.9 +/- 7.7 nmol/mumol and no control patient exceeded the mean by 2 standard deviations. There was no difference in the ratio between the sexes. Sixty-five per cent of colon cancer patients and 37.5 per cent of gastric and rectal cancer patients exceeded this upper limit of normality. There was no correlation between pseudouridine/creatinine ratio and histological differentiation, liver involvement or stage in either colorectal or gastric cancer patients. Urinary pseudouridine/creatinine ratio is one of the better non-specific cancer markers and may be particularly useful for detecting colonic cancer.

Pyrimidine nucleoside phosphorylase activity in tumour and matched normal gastrointestinal mucosa.

5-Fluorouracil (5-FU) requires activation to the metabolites FdUMP and FUTP for its cytotoxic effect. This activation involves the intracellular enzymes uridine and thymidine phosphorylase. We have assayed the levels of these enzymes in colorectal and gastric cancers and have shown that, in the majority of cases, the enzyme levels were higher than in the adjacent normal mucosa. It is suggested that, while the ratio tumour/normal mucosa enzyme activity may give some indication of the relative toxicity of 5-FU in these tissues, the absolute activities of the phosphorylases in tumour tissue could give a better indication of tumour responsiveness.