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Summary: Preparations of d,/-and meso-hexamethyl propyleneamine oxime (HM-PAO) labeled with techne tium-99m were added to rat brain homogenates diluted with phosphate buffer (l: 10). The conversion of d, / HM-PAO to hydrophilic forms took place with an initial rate constant of 0.12 min -1. Incubation of the brain ho mogenate with 2% diethyl maleate for 5 h decreased the homogenate's measured glutathione (GSH) concentration from 160 to 16 f.LM and decreased the conversion rate to 0.012 min -]. Buffered aqueous solutions of glutathione rapidly converted the HM-PAO tracers to hydrophilic forms having the same chromatographic characteristics as found in the brain homogenates. The rate constant for the conversion reaction of d,l-HM-PAO in GSH aqueous solution was 208 and 317 LlmoIlmin in two different assay systems and for meso-HM-PAO the values were 14.7 and 23.2 LlmoIlmin, respectively. Rat brain has a GSH con centration of about 2.3 mM and the conversion of the d,l-HM-PAO due to GSH alone should proceed with a Over the last decade, several brain imaging ra diopharmaceuticals with sufficiently long brain res idence times to permit routine imaging by single photon emission computed tomography (SPECT) have been developed. These have included e2 3 I]_ labeled p-iodo-N -isopropylamphetamine (IMP) (Winchell et aI., 1980) and N ,N-dimethyl-N'(2-hydroxy-5-iodo-3-methylbenzyl)-1 ,3-propanediamine (HIPDM) (Tramposch et aI., 1983), eOITl] diethyldithiocarbamate (DDC) (Wyth et aI., 1983)

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Leukocytes labeled with technetium-99m hexamethylpropyleneamine oxime (HMPAO) were used in 100 patients: 32 with suspected inflammatory bowel disease, 17 with fever of unknown origin, 21 with suspected abdominal sepsis, 20 with suspected bone sepsis, seven with bronchiectasis, and three with recent myocardial infarction. The distribution of activity in patients subsequently shown not to have inflammatory bowel disease was similar to that previously described for indium-111-labeled leukocytes. However, in this study, activity was also seen in the kidneys and bladder and occasionally the gallbladder on both early (1-3 hours) and late (24 hours) views, and in the colon in late views. Migration of Tc-99m-labeled granulocytes was seen in inflammatory disease as early as 30 minutes after injection, while normal bowel activity was not seen before 4 hours. The sensitivity of Tc99m-labeled leukocytes in the detection of inflammation was 100%, the specificity was 95%.

An investigation of the efficacy of astatine-211--tellurium colloid for the treatment of experimental malignant ascites in mice reveals that this alpha-emitting radiocolloid can be curative without causing undue toxicity to normal tissue. By comparison, negatron-emitting phosphorus-32 as colloidal chromic phosphate had no antineoplastic activity. The most compelling explanation for this striking difference is the dense ionization and short range of action associated with alpha-emission. These results have important implications for the development and use of alpha-emitters as radiocolloid therapy for the treatment of human tumors.

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Summary:The initial extraction (E) across the blood brain barrier (BBB) of [99mTc]-d,I-HM-PAO after intra carotid injection was measured in 14 Wistar rats and 6 patients using the double indicator, single injection method with Na-24 as the cotracer. In both series, cere bral blood flow (CBF) was measured using the initial slope of the xenon-133 washout curve after intracarotid bolus injection. In rats, bolus size (20 or 120 ILl), bolus type (saline or 10% albumin), or CBF were changed. First-pass extraction was dependent on CBF (p < 0.001): With a small bolus of saline and at resting CBF (0.75 mUg/min), E was 0.81, decreasing to 0.56 at a high CBF (1.5 ml/g/min). The calculated permeability surface area product (PS) increased linearly from 1.2 to 1.5 ml/g/min when CBF increased from 0.8 to 1.5 ml/g/min (p < 0.01).E was found to increase when the bolus volume of saline d,l-Hexamethylpropyleneamine oxime (d,l HM-PAO) chelated with technetium-99m has been developed as a tracer for measuring regional cere bral blood flow (rCBF) distribution in humans (Neirinckx et aI., 1987; Sharp et aI., 1985). The complex e9mTc-d,I-HM-PAO) is lipophilic and dif fuses across cell membranes including the blood brain barrier (BBB) and can thus enter the brain. With a molecular weight of 384 and an octanol water partition coefficient of 80 (Andersen et aI., 1988) , it could be expected that the initial uptake is close to 100% (Hansch et aI., 1967; Fenstermacher et aI., 1984; Dischino et aI., 1983; Levin et aI., 1980). However, is the exchange of d,l-HM-PAO across the BBB sufficiently rapid at all flow levels so as to Address correspondence and reprint requests to Dr. A. R. Andersen at Department of Neurology, N2081, Rigshospitalet, Blegdamsvej DK-2100, Copenhagen, Denmark. S44was increased from 20 to 120 ILl, while using a 120 ILl bolus containing 10% albumin resulted in a decrease in E. This suggests that HM-PAO binding to albumin is not totally and rapidly reversible during a single passage through brain capillaries and that binding to blood ele ments may reduce the apparent extraction across brain capillaries. In patients using a bolus of 1 ml saline, E decreased linearly with increasing CBF (r = -0.81, p < make the initial tracer uptake solely dependent on blood flow?In order to investigate some of the relevant phys iological properties of d,l-HM-PAO, we have mea sured the initial fractional uptake, the apparent ex traction (E) across the BBB, as a function of CBF in rats and in humans using the double indicator, sin gle injection method (Chinard et aI., 1955;Crone, 1963;Hertz and Paulson, 1983). With this method, the venous outflow concentrations of a diffusable test substance and of an impermeable reference substance indicate the extent of trans capillary loss that has occurred during a single passage following an intra-arterial injection of the tracers. The method also allows us to gain a qualitative assessment of HM-PAO backdiffusion (brain to blood) during the short experimental period. This phenomenon is well known for i...

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