Fischman Aj

Pharmacokinetics of [18F]fleroxacin in healthy human subjects studied by using positron emission tomography.

Positron emission tomography (PET) with [18F]fleroxacin was used to study the pharmacokinetics of fleroxacin, a new broad-spectrum fluoroquinolone, in 12 healthy volunteers (9 men and 3 women). The subjects were infused with a standard therapeutic dose of fleroxacin (400 mg) supplemented with approximately 20 mCi of [18F]fleroxacin. Serial PET images were made and blood samples were collected for 8 h, starting at the initiation of the infusion. The subjects were then treated with unlabeled drug for 3 days (400 mg/day). On the fifth day, infusion of radiolabeled drug, PET imaging, and blood collection were repeated. In most organs, there was rapid accumulation of radiolabeled drug, with stable levels achieved within 1 h after completion of the infusion. Especially high peak concentrations (in micrograms per gram) were achieved in the kidney (> 34), liver (> 25), lung (> 20), myocardium (> 19), and spleen (> 18). Peak concentrations of drug more than two times the MIC for 90% of Enterobacteriaceae strains tested (> 10-fold for most organisms) were achieved in all tissues except the brain and remained above this level for more than 6 to 8 h. The plateau concentrations in tissues (2 to 8 h, in micrograms per gram +/- standard error of the mean) of drug were as follows: brain, 0.83 +/- 0.032; myocardium, 4.53 +/- 0.24; lung, 5.80 +/- 0.48; liver, 7.31 +/- 0.33; spleen, 6.00 +/- 0.47; bowel, 3.53 +/- 0.74; kidney, 8.85 +/- 0.64; bone, 2.87 +/- 0.29; muscle, 4.60 +/- 0.33; prostate, 4.65 +/- 0.48; uterus, 3.87 +/- 0.39; breast, 2.68 +/- 0.11; and blood, 2.35 +/- 0.09. Concentrations of fleroxacin in tissue were similar in males and females, before and after pretreatment with unlabeled drug. Images

Pharmacokinetics of 18F-labeled fleroxacin in rabbits with Escherichia coli infections, studied with positron emission tomography.

18F-labeled fleroxacin was used to measure the pharmacokinetics of fleroxacin in healthy and infected animals by positron emission tomography (PET) and tissue radioactivity measurements. In all experiments, a pharmacological dose of unlabeled drug (10 mg/kg) was coinjected with the tracer. The pharmacokinetics of [18F]fleroxacin was measured in groups of healthy mice (n = six per group) at 10, 30, 60, and 120 min after injection and in groups of rats with Escherichia coli thigh infections (n = six per group) at 60 and 120 min after injection by radioactivity measurements in excised tissues. In healthy rabbits (n = 4) and in rabbits with E. coli thigh infections (n = 4), tissue concentrations of drug were determined by serial PET imaging over 2 h; after the final image was acquired, animals were sacrificed and concentrations measured by PET were compared with the results of tissue radioactivity measurements. In all three species, there was rapid equilibration of [18F]fleroxacin to significant concentrations in most peripheral organs; low concentrations of drug were detected in the brain. Accumulations of radiolabeled drug in infected and healthy thigh muscles were similar. Peak concentrations of drug of more than three times the MIC for 90% of members of the family Enterobacteriaceae (greater than 100-fold for most organisms) were achieved in all tissues except brain and remained above this level for more than 2 h. Especially high peak concentrations were achieved in the kidney (greater than 75 micrograms/g), liver (greater than 50 micrograms/g), blood (greater than 25 micrograms/g), and bone and lung (greater than 10 micrograms/g).Since the MICs for 90% of all Enterobacteriaceae are <2 micrograms/ml, fleroxacin should be particularly useful in treating gram-negative infections affecting these tissues. In contrast, the low concentration of drug delivered to the brain should limit the toxicity of the drug for the central nervous system. Images

Differentiation of regional perfusion and fatty acid uptake in zones of myocardial injury

The relative myocardial distribution of 201Tl and modified fatty acid (123I-labelled 3-methyl-p-[iodo]-phenyl pentadecanoic acid, MFA) was determined in eight patients with unstable angina (UA) and six patients with acute myocardial infarction treated with reperfusion therapy within 4.1 h (MI). The results of radionuclide imaging were correlated with coronary angiography and quantitative left ventriculography performed within 10 days of the radionuclide procedures. Zones of injury were identified as areas with diminished 201Tl uptake distal to sites of coronary narrowing. A nearly parallel reduction in regional fatty acid concentration was observed in these areas. Comparison of the regional distributions of the two agents revealed subtle differences in their distributions in the ischaemic zones. Three patterns were recognized: (a) MFA uptake greater than Tl (MFA greater than Tl), (b) matched decrease of MFA and Tl (MFA = Tl), (c) MFA uptake less than Tl (MFA less than Tl). Seven of eight patients with UA had normokinesis or hypokinesis on quantitative left ventriculography. Five of the seven showed the MFA greater than Tl pattern, while one had the MFA less than Tl pattern and one had the MFA = Tl pattern. The eighth patient with UA had akinesis and the MFA = Tl pattern. All six patients with acute infarction had akinesis on ventriculography. One of these patients had the MFA greater than Tl pattern, two had the MFA = Tl pattern and three had the MFA less than Tl pattern. These results suggest that fatty acid and thallium have grossly similar distributions in areas of acute myocardial ischaemia. On careful inspection, zones of slight relative excess fatty acid concentration are observed more often in areas of acute ischaemia with normal wall motion.

Detection of inflamed atherosclerotic lesions with diadenosine-5′,5‴-P1,P4-tetraphosphate (Ap4A) and positron-emission tomography

Diadenosine-5′,5‴-P1,P4-tetraphosphate (Ap4A) and its analog P2,P3-monochloromethylene diadenosine-5′,5‴-P1,P4-tetraphosphate (AppCHClppA) are competitive inhibitors of adenosine diphosphate-induced platelet aggregation, which plays a central role in arterial thrombosis and plaque formation. In this study, we evaluate the imaging capabilities of positron-emission tomography (PET) with P2,P3-[18F]monofluoromethylene diadenosine-5′,5‴-P1,P4-tetraphosphate ([18F]AppCHFppA) to detect atherosclerotic lesions in male New Zealand White rabbits. Three to six months after balloon injury to the aorta, the rabbits were injected with [18F]AppCHFppA, and microPET imaging showed rapid accumulation of this radiopharmaceutical in the atherosclerotic abdominal aorta, with lesions clearly visible 30 min after injection. Computed tomographic images were coregistered with PET images to improve delineation of aortoiliac tracer activity. Plaque macrophage density, quantified by immunostaining with RAM11 against rabbit macrophages, correlated with PET measurements of [18F]AppCHFppA uptake (r = 0.87, P < 0.0001), whereas smooth-muscle cell density, quantified by immunostaining with 1A4 against smooth muscle actin, did not. Biodistribution studies of [18F]AppCHFppA in normal rats indicated typical adenosine dinucleotide behavior with insignificant myocardial uptake and fast kidney clearance. The accumulation of [18F]AppCHFppA in macrophage-rich atherosclerotic plaques can be quantified noninvasively with PET. Hence, [18F]AppCHFppA holds promise for the noninvasive characterization of vascular inflammation.

The use of pentafluorophenyl derivatives for the 18F labelling of proteins

A simple, one-step method for the radiolabelling of proteins with 18F is described. A series of pentafluorophenyl derivatives were synthesized and tested for 18F exchange using tetrabutylammonium-[18F]fluoride in DMSO, with microwave heating. A number of the compounds examined incorporated 18F quickly and in high yield. Two compounds, pentafluorobenzaldehyde and 2,3,5,6-tetrafluorophenylpentafluorobenzoate, were used to label HSA in good yield. The methods produce low specific activity labelled proteins, but are fast. The yields are reasonable and the reagents do not require a separate modification or activation step for protein labelling.

7,10-Bis(2-mercapto-2-methyl)propyl-7,10-diazapalmitic acid: a novel, N2S2 ligand for technetium-99m

7,10-Bis(2-mercapto-2-methyl)propyl-7,10-diazapalmitic acid (7) was synthesized and evaluated as a new ligand for technetium-99m (99mTc). The title fatty acid analog, an achiral, bis(aminoethanethiol) derivative in which the amines are tertiary, gave a stable complex with 99mTc. The biodistribution of 99mTc-labeled 7 in rats is reported.