Plasma cholecystokinin concentrations in 3-day-old lambs: effect of the duration of fasting preceding a sucking bout

Determination of tissue perfusion rates by MRI bolus tracking methods relies on the central volume principle which states that tissue blood flow is given by the tissue blood volume divided by the mean tracer transit time (MTT). Accurate determination of the MTT requires knowledge of the arterial input function which in MRI experiments is usually not known, especially when using small animals. The problem of unknown arterial input can be circumvented in animal experiments by directly injecting the contrast agent into a feeding artery of the tissue of interest. In the present article the passage of magnetite nanoparticles through the rat cerebral cortex is analyzed after injection into the internal carotid artery. The results are discussed in the framework of linear system theory using a one-compartment model for brain tissue and by using the well characterized gamma-variate function to describe the tissue concentration profile of the contrast agent. The results obtained from the intra-arterial tracer administration experiments are then compared with the commonly used intra-venous injection of the contrast agent in order to estimate the contribution of the peripheral circulation to the MTT values in the latter case. The experiments were analyzed using a two-compartment model and the gamma-variate function. As an application perfusion rates in normal and ischemic cerebral cortex of hypertensive rats were estimated in a model of focal cerebral ischemia. The results indicate that peripheral circulation has a significant influence on the MTT values and thus on the perfusion rates, which cannot be neglected.     

Magnetic resonance imaging of perfusion in the isolated rat heart using spin inversion of arterial water

Measurement of regional myocardial perfusion is important for the diagnosis and treatment of coronary artery disease. Currently used methods for the measurement of myocardial tissue perfusion are either invasive or not quantitative. Here, we demonstrate a technique for the measurement of myocardial perfusion using magnetic resonance imaging (MRI) with spin tagging of arterial water. In addition, it is shown that changes in perfusion can be quantitated by measuring changes in tissue T1. Perfusion images are obtained in Langendorff-perfused, isolated rat hearts for perfusion rates ranging from 5 to 22 ml/g/min. The MRI-determined perfusion rates are in excellent agreement with perfusion rates determined from measurement of bulk perfusate flow (r = 0.98). The predicted linear dependence of the measured T1 (T1app) on perfusion is also demonstrated. The ability of perfusion imaging to measure regional variations in flow is demonstrated with hearts in which perfusion defects were created by ligation of a coronary artery. These results indicate that MRI of perfusion using spin inversion of arterial water gives quantitative maps of cardiac perfusion.     

Immunological and trophical effects of Saccharomyces boulardii on the small intestine in healthy human volunteers

Recently we investigated the mechanisms mediating the transport of valproic acid (VPA) between blood and brain. In one study efflux of valproic acid (VPA) from rabbit brain was inhibited by probenecid. Efflux of VPA decreased when probenecid was given intravenously but not when probenecid was given by ventriculocisternal (VC) perfusion indicating that the major site of probenecid-sensitive transport was at the brain capillary endothelium and not at the choroid plexus. In another study VPA transport into rat brain was inhibited by para-aminohippurate (PAH). The purpose of the present study were to determine (a) if the efflux of VPA from rabbit brain was also inhibited by PAH, and (b) whether efflux of VPA could occur at the choroid plexus via an PAH-selective transport system. Six control rabbits received VPA by intravenous infusion and tracer concentrations of [3H]VPA and [14C]PAH by VC perfusion. Rabbits in the PAH group (n = 6) received identical treatment with VPA, tracer concentrations of [3H]VPA and [14C]PAH and, in addition, received 20 mM PAH by VC perfusion. PAH had no effect on the VC extraction ratio of [3H]VPA or the steady-state brain concentration of intravenously administered VPA. It is concluded that the efflux of VPA at the rabbit blood-brain barrier is mediated by a transporter different from the PAH-like transporter responsible for the uptake of VPA into rat brain. In addition, the finding that VC perfusion with PAH had no effect on the VC extraction of [3H]VPA provides further evidence that the choroid plexus plays a negligible role in removal of VPA from the CNS.     

Positron emission tomography in primary brain tumours using cobalt-55

Primary brain tumours are usually assessed by computed tomography (CT) and magnetic resonance imaging (MRI), sometimes in conjunction with positron emission tomography (PET). We used cobalt-55 (55Co) as a calcium (Ca) tracer to visualize decaying tumour tissue, based on the fact that Ca-influx is essential in both cell death and leukocyte activation. Net 55Co uptake may be the result of cell decay, leukocyte infiltration, (re)perfusion and the pharmacological profile of 55Co. Three patients with primary malignant brain tumours (first presentation) were studied with CT, MRI and Co-PET after the intravenous administration of 0.5 mCi 55Co. Histopathological diagnosis was obtained by biopsy or resection. Co-PET demonstrated each of the brain tumours and showed good topographical agreement with CT and MRI. Co-PET provided additional detail as to the site and size of the necrotic core and the perinecrotic rim of decaying tumour. The 55Co uptake indices varied between 2.6 and 5.3. 55Co demonstrated uptake in decaying tissue, irrespective of the integrity of the blood-brain barrier. Neither necrotic nor viable tumour tissue showed affinity for 55Co. Since 55Co is readily applicable to both PET and single photon emission tomography (SPET), differences in the uptake mechanism and functional significance of the 55Co tracer are discussed in relation to 201Tl SPET. We present a (limited) pilot series of three patients to forward the claim of this new functional technique in nuclear neurology.     

Identification of a saturable uptake system for deoxyribonucleosides at the blood-brain and blood-cerebrospinal fluid barriers

Substances can enter the brain either directly across the blood-brain barrier or indirectly across the choroid plexuses and arachnoid membrane (blood-CSF barrier) into the CSF and then by diffusion into the brain. Earlier studies have demonstrated a saturable thymidine uptake across the blood-CSF barrier, but not across the blood-brain barrier. In this study transport of [3H]thymidine across both barriers was measured in vivo by means of a bilateral vascular brain perfusion technique in the anaesthetised guinea-pig. This method allows simultaneous and quantitative measurement of slowly penetrating solutes into both brain and CSF, under controlled conditions of arterial inflow. The results of the present study carried out over perfusion periods of up to 30 min indicated a progressive uptake of [3H]thymidine into brain and CSF, which was found to be significantly greater than the transport of D-[14C]mannitol (a plasma space marker). Furthermore, the addition of 1 mM unlabelled thymidine in the perfusate caused saturation of [3H]thymidine uptake into both brain and CSF. In conclusion, these findings suggest that thymidine can cross both the blood-brain and blood-CSF barriers in the guinea-pig by carrier-mediated transport systems.     

Quantitative microdialysis of ethanol in rat striatum

We have applied a steady-state theory of microdialysis to characterize the diffusion of ethanol through a microdialysis membrane and through rat striatum. Quantitative characterization required measurement of in vitro and in vivo extraction fractions for ethanol and determination of the clearance of ethanol from brain tissue during steady-state perfusion through a microdialysis probe. Extraction fraction of ethanol was determined in vitro by perfusing a known concentration of ethanol through probes immersed in water at 37 degrees C with stirring. The in vitro extraction fraction yielded a probe permeability value of 0.046 +/- 0.004 cm/min that is comparable with an estimate from published measurements for similar dialysis membranes. The in vivo extraction fraction was determined for probes placed in the striatum. Clearance of ethanol and a brain slice concentration profile of ethanol were determined by measurement of the amount of ethanol remaining in the brain tissue during steady-state perfusion of the probe. Steady state was achieved within 10 min after beginning the ethanol perfusion in vivo, and the extraction fraction was not altered by sedation of the rat with pentobarbital. The tissue concentration profile was symmetrical around the probe track, and ethanol was detected 1 mm from the probe. The experimental clearance rate constant value obtained for ethanol (2.0 +/- 0.3 min(-1)) was higher than that expected for removal solely by loss to the blood. The tissue diffusivity for ethanol, Dt, derived from the experimental measurements was 1.2 +/- 0.2 x 10(-5) cm2/sec. This value is greater than expected for interstitial diffusion, suggesting a substantial contribution by transcellular diffusion of ethanol as well. The predicted tissue concentration profile had a higher peak value and did not extend into the tissue (0.5 mm) as much as the experimental profile (1 mm), although there was reasonable agreement between experiment and theory. Our quantitative characterization of the microdialysis behavior of ethanol in brain provides a framework for interpretation of brain microdialysis experiments using ethanol by supplying, inter alia, a means for estimating the ethanol concentration achieved in the tissue volume being sampled by the probe.     

Quantitative evaluation of the blood-brain barrier capacity to form dopamine from circulating L-DOPA

The ability of the blood-brain barrier to form dopamine from increasing doses of systemically administered L-DOPA has been studied in rats by a combination of chemical determination of dopamine, and histochemical and cytofluorometric measurements of L-DOPA and dopamine. The break-through of L-DOPA from the circulation into the brain parenchyma via the enzymatic blood-brain barrier was estimated by comparing the amount of newly formed dopamine in the caudate nucleus-putamen and in the cerebellum. The capillaries were found to efficiently trap L-DOPA in their walls, and an upper limit was reached (at an administered i.p. dose of 100 mg/kg of L-DOPA). It could be estimated that approximately 3% of the total dose of L-DOPA given was decarboxylated by the blood-brain barrier. The possible influence by the regional differences in perfusion of the two regions seen after administration of L-DOPA was ruled out in measurements of local cerebral blood flow using the 14C-ethanol technique.     

Glucose transporter expression in brain: relationship to cerebral glucose utilization

Glucose is the principle energy source for mammalian brain. Delivery of glucose from the blood to the brain requires its transport across the endothelial cells of the blood-brain barrier and across the plasma membranes of neurons and glia, which is mediated by the facilitative glucose transporter proteins. The two primary glucose transporter isoforms which function in cerebral glucose metabolism are GLUT1 and GLUT3. GLUT1 is the primary transporter in the blood-brain barrier, choroid plexus, ependyma, and glia; GLUT3 is the neuronal glucose transporter. The levels of expression of both transporters are regulated in concert with metabolic demand and regional rates of cerebral glucose utilization. We present several experimental paradigms in which alterations in energetic demand and/or substrate supply affect glucose transporter expression. These include normal cerebral development in the rat, Alzheimer's disease, neuronal differentiation in vitro, and dehydration in the rat.     

Activation of protein kinase C does not participate in disruption of the blood-brain barrier to albumin during acute hypertension

The blood-brain barrier minimizes the entry of macromolecules into brain tissue. During acute increases in arterial blood pressure, disruption of the blood-brain barrier occurs primarily in cerebral venules and veins. Mechanisms by which increases in cerebral venous pressure produce disruption of the blood-brain barrier during acute hypertension are not clear. The goal of this study was to determine the role of activation of protein kinase C in disruption of the blood-brain barrier during acute hypertension. We examined the microcirculation of the cerebrum in vivo. Permeability of the blood-brain barrier was quantitated by the formation of venular leaky sites and clearance of fluorescent-labeled albumin (FITC-albumin) before and during phenylephrine-induced acute hypertension. In addition, we examined changes in pial arteriolar and pial venular pressure before and during phenylephrine-induced acute hypertension. We compared responses of the blood-brain barrier to acute hypertension in control (untreated) rats and in rats treated with inhibitors of protein kinase C; calphostin C (0.1 microM) or sphingosine (1.0 microM). Under control conditions, no venular leaky sites were visible and clearance of FITC-albumin was minimal in all groups. Phenylephrine infusion increased systemic arterial, pial arteriolar and pial venular pressures, and increased the formation of venular leaky sites and clearance of FITC-albumin by a similar magnitude in all groups. The findings of the present study suggest that inhibition of protein kinase C does not significantly alter the formation of venular leaky sites and/or clearance of FITC-albumin during acute hypertension. Thus, disruption of the blood-brain barrier during acute hypertension does not appear to be influenced by activation of protein kinase C.     

Lack of autoregulatory response of the cerebral circulation after osmotic opening of the blood-brain barrier in dogs

The reversibility of osmotic opening of the blood-brain barrier was studied in dogs one hour after intracarotid 3 M urea injection. At that time the permeability of cerebral blood vessels to albumin is restored as evidenced by lack of Evans blue extravasation. Despite that, the response of the urea-perfused hemisphere to changes of perfusion pressure was abnormal. Blood flow in that hemisphere followed passively blood pressure changes in contrast to the contralateral hemisphere in which the blood flow remained independent of the perfusion pressure.     

11C-methionine PET for differential diagnosis of low-grade gliomas

Management of low-grade gliomas continues to be a challenging task, because CT and MRI do not always differentiate from nontumoral lesions. Furthermore, tumor extent and aggressiveness often remain unclear because of a lack of contrast enhancement. Previous studies indicated that large neutral amino acid tracers accumulate in most brain tumors, including low-grade gliomas, probably because of changes of endothelial and blood-brain barrier function. We describe 11C-methionine uptake measured with PET in a series of 196 consecutive patients, most of whom were studied because of suspected low-grade gliomas. Uptake in the most active lesion area, relative to contralateral side, was significantly different among high-grade gliomas, low-grade gliomas, and chronic or subacute nontumoral lesions, and this difference was independent from contrast enhancement in CT or MRI. Corticosteroids had no significant effect on methionine uptake in low-grade gliomas but reduced uptake moderately in high-grade gliomas. Differentiation between gliomas and nontumoral lesions by a simple threshold was correct in 79%. Recurrent or residual tumors had a higher uptake than primary gliomas. In conclusion, the high sensitivity of 11C-methionine uptake for functional endothelial or blood-brain barrier changes suggests that this tracer is particularly useful for evaluation and follow-up of low-grade gliomas.     

Compound heterozygosity for an out-of-frame deletion and a splice site mutation in the LAMB3 gene causes nonlethal junctional epidermolysis bullosa

OBJECTIVE: To explore the temporal relation of demyelination and blood-brain barrier breakdown during new lesion formation. BACKGROUND: Conventional MRI appears sensitive for detecting changes due to MS, but may be limited by poor pathologic specificity. By indirectly assessing protons bound to rigid macromolecules, magnetization transfer (MT) imaging may provide information relating to tissue structure and, by inference, myelin integrity. METHODS: Gadolinium contrast-enhanced MRI and MT imaging were performed at weekly intervals for 3 months in three patients with MS. For each enhancing lesion, the largest corresponding area of proton density hyperintensity seen during the study was outlined and magnetization transfer ratio (MTR) calculated at each time point from coregistered calculated MTR images. Lesions greater than 20 mm2, not affected by partial volume effects, and first enhancing after the baseline study were analyzed. Two-dimensional registration software allowed accurate evaluation of MTR in regions both before and after the initial appearance of MS lesions. RESULTS: Mean lesion MTR decreased significantly during the first week of enhancement (29.6 percent units [pu] immediately pre-enhancement versus 28.2 pu at first documented stage of enhancement). No significant MTR reduction was noted before this. CONCLUSION: The lack of observable change in MTR before the first detectable gadolinium enhancement within MS lesions suggests that blood-brain barrier disruption is closely related to, but not preceded by, demyelination.     

Pharmacokinetics of triptorelin after intravenous bolus administration in healthy males and in males with renal or hepatic insufficiency

PURPOSE: The aim of the present study was to validate a simple MRI-procedure for semiquantitative assessment of regional cerebral blood flow. MATERIALS AND METHODS: Unilateral cerebral ischaemia (30 minutes) in the territory of the middle cerebral artery was induced in 14 anesthetised rates. The MRI-experiment consisted in an intravenous bolus injection of gadolinium-DTPA, recording of the cerebral contrast kinetics with a T2*-weighted pulse sequence, and measurement of the maximal concentration change at a chosen reference point of time. To measure perfusion quantitatively, a microsphere technique, an accepted reference technique was used. With both methods a perfusion index related to the contralateral side was calculated. RESULTS: In all cases decreased perfusion was detected by the MRI technique. The perfusion indices correlated with a coefficient of correlation of r = 0.89 (p < 0.001). CONCLUSION: The results demonstrate that contrast-enhanced MRI with bolus injection can be implemented with clinical potential as a semiquantitative instrument for the assessment of cerebral perfusion. Regional cerebral blood volume and collateral blood flow may interfere with the estimate of blood flow.     

In vivo quantitative mapping of cardiac perfusion in rats using a noninvasive MR spin-labeling method

Measurement of myocardial perfusion is important for the functional assessment of heart in vivo. Our approach is based on the modification of the longitudinal relaxation time T1 induced by magnetic spin labeling of endogenous water protons. Labeling is performed by selectively inverting the magnetization within the detection slice, and longitudinal relaxation is measured using a fast gradient echo MRI technique. As a result of blood flow, nonexcited spins enter the detection slice, which leads to an acceleration of the relaxation rate. Incorporating this phenomenon in a mathematical model that describes tissue as two compartments yields a simple expression that allows the quantification of perfusion from a slice-selective and a global inversion recovery experiment. This model takes into account the difference between T1 in blood and T1 in tissue. Our purpose was to evaluate the feasibility and reproducibility of this technique to map quantitatively myocardial perfusion in vivo in rats. Quantitative maps of myocardial blood flow were obtained from nine rats, and the reproducibility of the technique was evaluated by repeating the whole perfusion experiment four times. Evaluation of regions of interest within the myocardium yielded a mean perfusion value of 3.6 +/- .5 ml x min(-1) x g(-1) over all animals, which is in good agreement with previously reported literature values.     

Defining the critical limit of oxygen extraction in the human small intestine

Although animal models have been used to characterize the relation between oxygen consumption and blood flow, reliable data have not been generated in the human small intestine. We perfused segments of human small intestine by using an ex vivo perfusion circuit that allowed precise manipulation of blood flow and perfusion pressure. Our goal was to define the critical level of intestinal blood flow necessary to maintain the metabolic needs of the tissue. Human small intestine (n = 5) tissue obtained at transplantation harvest was transported on ice to the laboratory. A 40-cm mid-jejunal segment was selected for perfusion, and appropriate inflow and outflow vessels were identified and cannulated. Perfusion with an autologous blood solution was initiated through an extracorporeal membrane oxygenation circuit. After a 30-minute equilibration period, arterial and venous blood gases were measured at varying flow rates while maintaining a constant hematocrit level. Arterial and venous oxygen content, arteriovenous oxygen difference (A-VO2 diff), and oxygen consumption (VO2) were then calculated. Our results demonstrated that at blood flows > 30 ml/min/100 g, VO2 is independent of blood flow (1.6 +/- 0.06 ml/min/100 g), and oxygen extraction is inversely related to flow. Below this blood flow rate of 30 ml/min/100 g, oxygen extraction does not increase further (6.3 +/- 0.3 vol%), and VO2 becomes flow dependent. This ex vivo preparation defines for the first time a threshold value of blood flow for small intestine below which oxygen consumption decreases (30 ml/min/100 g). Previous animal studies have correlated such a decrease in oxygen consumption with functional and histologic evidence of tissue injury. This "critical" flow rate in human intestine is similar to that found previously in canine and feline intestine, but lower than that of rodent species.     

Proton T1rho-dispersion imaging of rodent brain at 1.9 T

Detection of H2(17)O with proton T1rho-dispersion imaging holds promise as a means of quantifying metabolism and blood flow with MRI. However, this technique requires a priori knowledge of the intrinsic T1rho dispersion of tissue. To investigate these properties, we implemented a T1rho imaging sequence on a 1.9-T Signa GE scanner. A series of T1rho images for different locking frequencies and locking durations were obtained from rat brain in vivo and compared with 5% (wt/vol) gelatin phantoms containing different concentrations of (17)O ranging from .037% (natural abundance) to 2.0 atom%. Results revealed that, although there is considerable T1rho-dispersion in phantoms doped with H2(17)O, the T1rho of rat brain undergoes minimal dispersion for spin-locking frequencies between .2 and 1.5 kHz. A small degree of T1rho dispersion is present below .2 kHz, which we postulate arises from natural-abundance H2(17)O. Moreover, the signal-to-noise ratios of T1rho-weighted images are significantly better than comparable T2-weighted images, allowing for improved visualization of tissue contrast. We have also demonstrated the feasibility of proton T1rho-dispersion imaging for detecting intravenous H2(17)O on a live mouse brain. The potential application of this technique to study brain perfusion is discussed.     

The effects of the HIV-1 envelope protein gp120 on the production of nitric oxide and proinflammatory cytokines in mixed glial cell cultures

Previous studies showed that intracarotid artery perfusion of biotinylated vasoactive intestinal peptide analog (bio-VIPa) coupled to a blood-brain barrier (BBB) drug delivery vector, OX26/avidin, causes an increase in brain blood flow by 65% in N2O-anesthetized rats. OX26 is a murine monoclonal antibody to the rat transferrin receptor and undergoes receptor-mediated transport through the BBB in vivo. The present investigation examined the central nervous system effects of bio-VIPa after conventional i.v. injection to conscious rats. The VIPa was monobiotinylated (bio) with an-XX-noncleavable (amide) linker, and the bio-XX-VIPa conjugated to OX26/streptavidin (SA) maintained affinity for the VIP receptor in radioreceptor assays. Brain uptake of the bio-XX-VIPa coupled to the OX26/SA vector after i.v. injection was at least 10-fold higher than that of the free bio-XX-VIPa, because of both an increased plasma area under the concentration curve and BBB permeability-surface area product. Administration of the free bio-XX-VIPa increased salivary gland blood flow by 350%, but had no effect on brain blood flow. By contrast, bio-XX-VIPa/OX26-SA conjugate at equal doses (20 micrograms/kg) after i.v. injection increased brain blood flow by 60% in conscious rats, but had no effect on salivary gland blood flow. In summary, the use of the BBB peptide drug delivery system targeted the drug to the central nervous system, and optimized the therapeutic index of the VIPa by enhancing cerebral blood flow and by attenuating side effects in peripheral organs such as salivary gland.     

Construction of a physiologically based pharmacokinetic model for 2,4-dichlorophenoxyacetic acid dosimetry in the developing rabbit brain

A physiologically based pharmacokinetic (PBPK) model that describes the kinetics of organic anions by using 2,4-dichlorophenoxyacetic (2,4-D) as a representative compound was constructed for the developing rabbit brain at near-term pregnancy (Gestation Day 30). The model consisted of brain, body, and venous and arterial compartments for the mother which were linked to the fetus by a placenta. Maternal brain compartments in the model were brain plasma, cerebrospinal fluid (CSF), and brain tissue including hypothalamus, caudate nucleus, hippocampus, forebrain, brainstem, and cerebellum. The fetus consisted of brain, body, amniotic fluid, and venous and arterial compartments. the maternal body had both a central and a deep compartment; the fetal body had only one compartment. Maternal blood flow to the fetus was modeled as blood flowing to the placenta, where it was equilibrated before it reached the fetus. The brain uptake was membrane-limited by the blood-brain barrier, with saturable clearance from the CSF into the venous blood by the choroid plexus in both fetus and mother. The model was used to compare concentrations of 2,4-D in maternal and fetal brain, maternal and fetal plasma, and amniotic fluid over time with experimental data from pregnant rabbits given 2,4-D intravenously (1, 10, or 40 mg/kg). The model adequately simulated the 2-hr time course of 2,4-D concentrations in both mother and fetus. With continued development, this generic PBPK model should be a useful tool for evaluating the safety of organic acid neurotoxicants in the developing brain.     

Measurement of kinetic perfusion parameters of gadoteridol in intact myocardium: effects of ischemia/reperfusion and coronary vasodilation

Quantitation of myocardial perfusion is feasible using contrast enhanced magnetic resonance imaging. A method to quantitate myocardial blood flow is provided by the Kety model modified to account for a diffusable tracer such as gadoteridol. In the present study, perfusion parameters of the modified Kety model (partition coefficient and extraction efficiency) were determined for gadoteridol in intact myocardium using a constant flow, isolated, perfused heart model. Perfusion conditions included hearts with normal perfusion, hearts made globally ischemic for 20 min then perfused normally, and hearts whose coronary flow was more than doubled with 9 microM adenosine. T1 relaxation times were rapidly measured at 0.5 T following step increases in perfusate gadoteridol concentration and at steady state. Both the partition coefficient and extraction efficiency were found to be significantly increased in ischemic/reperfused hearts compared to normal. While flow rates in adenosine hearts were too high for accurate extraction efficiency determination using this technique, the partition coefficient was no different between adenosine and normally perfused hearts. The method described in this article allowed the kinetic parameters of the modified Kety model to be determined in intact heart using NMR relaxation time measurements as the basis of the calculation.     

Cytotoxicity of the anticancer agents cisplatin and taxol during cell proliferation and the cell cycle

The cerebral extraction and retention of three radioiodinatéd SPECT perfusion tracers were measured using residue detection in a baboon. A permeability-surface area product PS' with special relevance to SPECT was calculated from the retention of tracer in the brain after 10 min. PS' differs from the traditional PS value, which is calculated from the tracer clearance curve at 2 min. The PS' values ranged from 50 to 95 mL/min/100 g, decreased in the order [123I]IMP > [123I]iodoperidol approximately [123I]HIPDM, and did not differ for specific activities of 10 MBq/mmol to 74 TBq/mmol. These radioiodinated compounds exhibited extraction characteristics superior to those of [99mTc]HMPAO but underestimated cerebral blood flow when flows were above 20-30 mL/min/100 g, underscoring the need for development of a more ideal SPECT perfusion tracer.