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The extraction of 11C-labeled methanol, ethanol, and isopropanol, as well as 15O-labeled water by the brain during a single capillary transit, was studied in vivo in six adult rhesus monkeys by external detection of the time course of these tracers subsequent to their internal carotid artery injection. The data demonstrate the feasibility of accurately measuring brain permeability of highly diffusible substances by this technique and show that neither water nor the alcohols studied freely equilibrate with brain when the cerebral blood flow exceeds 30 ml/100 g min-1. At a cerebral blood flow of 50 ml/100 g min-1 only about 93% of an injected bolus of labeled water freely exchanges with brain, compared with methanol (93%), ethanol (97%), and isopropanol (99%). The brain capillary permeability-surface area (PS) products computed from these data were 0.023 cm3/s g-1 (water), 0.024 cm3/s g-1 (methanol), 0.030 cm3/s g-1 (ethanol), and 0.062 cm3/s g-1 (isopropanol). This sequence of PS products is consistent with the individual lipid solubilities of the alcohols studied and underscores the unique brain permeability characteristics of lipid-insoluble water.

The radiopharmaceutical glucose--11C was used in vivo measurement of brain-glucose transport kinetics and metabolism in the rhesus monkey. Radiotracer was injected intravenously as a bolus. Radioactivity was continuously recorded from the head and from the arterial blood via an indwelling peripheral artery catheter for a collectionperiod of 2-3 min. To correct the reading obtained from the head for radioactivitycontained in blood, a second intravenous injection of the vascular tracer -15O-labeled carboxyhemoglobin was used. The method was tested in nine phencyclidine-anesthetized monkeys in which cerebral glucose metabolism (CMRGlc) was simultaneously measured by our method and by a standard method emplying the Fick principle. A highlysignificant correlation was found between the two methods of measuring CMRGlc (r =0.929). In addition, our model predicted a ratio of forward-to-reverse glucose flux across the blood-brain barrier (BBR) (1.37 plus or minus 0.23 SD), the brain-to-bloodglucose concentration ratio across the BBB (0.633 plus or minus 0.14), the relative tissue free-glucose space (17 plus or minus 7%), the brain free-glucose concentration (13.6plus or minus 8.5 mg/100 g of tissue), and the brain free-glucose turnover time (2.96 plus or minus 1.98 min). author

We previously developed a non-steady-state technique using positron emission tomography (PET) and the radioligand 18F-spiperone (18F-SP) for the measurement of in vivo radioligand-receptor binding in brain. The purpose of this investigation is to determine the sensitivity of this method to alterations in the apparent number of available specific binding sites. Nine studies were performed on the same baboon. The animal was pretreated with varying doses of unlabeled SP (15-600 micrograms) to compete for specific binding sites. The experimental procedure included measurement of regional cerebral blood flow, cerebral blood volume, and the protein binding of 18F-SP in arterial blood. At least 3.5 hr after pretreatment, no-carrier-added 18F-SP (containing less than 3 micrograms SP) was administered intravenously. Sequential PET scans and measurements of arterial-blood radioactivity due to radioligand and its labeled metabolites continued for 3 hr. A 3-compartment model representing the in vivo behavior of radioligand was used to analyze the data. As expected, we found that an index of binding called the combined forward rate constant (which equals the product of the apparent maximum number of available specific binding sites and the association rate constant of radioligand for receptor) declined with increasing dose of unlabeled SP. Other estimated variables including the dissociation rate constant did not change. This demonstrates that our non-steady-state method for estimating radioligand-receptor binding kinetics can detect a decrease in the apparent number of available specific binding sites. This is an important step in the validation of this in vivo receptor binding assay and its subsequent application.