Brain Uptake Ratio Research Articles

Pituitary Incidentalomas Detected with Technetium-99m MIBI in Patients with Suspected Parathyroid Adenoma: Preliminary Results

Tc-99m MIBI (MIBI) is a cationic lipophilic agent, which has traditionally been used for myocardial perfusion scintigraphy, detection and monitoring of different benign and malignant tumors. The objective of this study was to evaluate the frequency of pituitary incidentalomas detected on MIBI scans performed on patients with suspected parathyroid adenomas and to provide semiquantitative analysis of tracer uptake in the pituitary region. Tomographic images of MIBI scans on 56 patients with suspected parathyroid adenomas (2006–2007) were analyzed retrospectively. Semiquantitative analysis of abnormal uptake was performed by drawing identical regions of interest (ROI) over the pituitary area and the normal brain on one transverse section that demonstrates the lesion most clearly. Pituitary uptake to normal brain uptake ratio was calculated in all cases. We found statistically significant differences of MIBI uptake in patients with pituitary adenomas, mean ratio: 29.78±12.17 (median 29.77, and range 19-41), compared with patients with no pathologic changes in this region, mean ratio was 5.88±1.82 (median was 5.95 and range 2.0- 9.2). As the groups are too small for statistical analysis, these results need to be confirmed in a larger cohort and should include more detailed biochemical correlation. MIBI parathyroid scintigraphy should be taken into account as a potential source of identifying pituitary incidentalomas. Clinical significance of these findings needs further evaluation.

Determination of the Optimal ROI Setting Position of the Input Function for the 99mTc-ethyl Cysteinate Dimmer Brain Uptake Ratio Method

Determination of the input function for the (99m)Tc-ethyl cysteinate dimmer brain uptake ratio ((99m)Tc-ECD BUR) method as a non-invasive quantitative measurement of cerebral blood flow measurement is of critical importance in order to improve the accuracy of this method. The input functions were experimentally obtained by setting the regions of interest (ROIs) in the ascending aorta, aortic arch, and descending aorta on the 49 chest RI-angio images. rCBFs by the BUR method with 3 input functions of the 6 cases were compared with those by the (123)I-iodoamphetamine (IMP) continuous arterial blood sampling method in order to determine the best location for the ROI of the input function. The input function of the ascending aorta was higher than those of the aortic arch and the descending aorta. The input functions of the aortic arch and the descending aorta decreased due to the origin of the three branches of the right brachiocephalic artery, left subclavian artery, and left common carotid artery. A good correlation was found in the regional cerebral blood flow (rCBF) values between the (123)I-IMP continuous arterial blood sampling method and the (99m)Tc-ECD BUR method with the input function of the ascending aorta. Therefore, the ascending aorta is the best location for the ROI of the input function for the (99m)Tc-ECD BUR method.

Imaging, Autoradiography, and Biodistribution of188Re-Labeled PEGylated Nanoliposome in Orthotopic Glioma Bearing Rat Model

The (188)Re-labeled pegylated nanoliposome (abbreviated as (188)Re-Liposome) was prepared and evaluated for its potential as a theragnostic agent for glioma. (188)Re-BMEDA complex was loaded into the pegylated liposome core with pH 5.5 ammonium sulfate gradient to produce (188)Re-Liposome. Orthotopic Fischer344/F98 glioma tumor-bearing rats were prepared and intravenously injected with (188)Re-Liposome. Biodistribution, pharmacokinetic study, autoradiography (ARG), histopathology, and nano-SPECT/CT imaging were conducted for the animal model. The result showed that (188)Re-Liposome accumulated in the brain tumor of the animal model from 0.28%±0.09% injected dose (ID)/g (n=3) at 1 hour to a maximum of 1.95%±0.35% ID/g (n=3) at 24 hours postinjection. The tumor-to-normal brain uptake ratio (T/N ratio) increased from 3.5 at 1 hour to 32.5 at 24 hours. Both ARG and histopathological images clearly showed corresponding tumor regions with high T/N ratios. Nano-SPECT/CT detected a very clear tumor image from 4 hours till 48 hours. This study reveals the potential of (188)Re-Liposome as a theragnostic agent for brain glioma.

Analysis of11C-methionine Uptake in Low-Grade Gliomas and Correlation with Proliferative Activity

The relationship of (11)C-methionine (MET) uptake and tumor activity in low-grade gliomas (those meeting the criteria for World Health Organization [WHO] grade II gliomas) remains uncertain. The aim of this study was to compare MET uptake in low-grade gliomas and to analyze whether MET positron-emission tomography (PET) can estimate tumor viability and provide evidence of malignant transformation. We studied glioma metabolic activity in 49 consecutive patients with newly diagnosed grade II gliomas by using MET PET before surgical resection. On MET PET, we measured tumor/normal brain uptake ratio (T/N ratio) in 21 diffuse astrocytomas (DAs), 12 oligodendrogliomas (ODs), and 16 oligoastrocytomas (OAs). We compared MET T/N ratio among these 3 tumors and investigated possible correlation with proliferative activity, as measured by Mib-1 labeling index (LI). MET T/N ratios of DA, OD, and OA were 2.11 +/- 0.87, 3.75 +/- 1.43, and 2.76 +/- 1.27, respectively. The MET T/N ratio of OD was significantly higher than that of DA (P < .005). In comparison of MET T/N ratios with the Mib-1 LI, a significant correlation was shown in DA (r = 0.63; P < .005) but not in OD and OA. MET uptake in DAs may be closely associated with tumor viability, which depends on increased amino acid transport by an activated carrier-mediated system. DAs with lower MET uptake were considered more quiescent lesions, whereas DA with higher MET uptake may act more aggressively.

Metabolic Assessment of Gliomas Using11C-Methionine, [18F] Fluorodeoxyglucose, and11C-Choline Positron-Emission Tomography

Positron-emission tomography (PET) is a useful tool in oncology. The aim of this study was to assess the metabolic activity of gliomas using (11)C-methionine (MET), [(18)F] fluorodeoxyglucose (FDG), and (11)C-choline (CHO) PET and to explore the correlation between the metabolic activity and histopathologic features. PET examinations were performed for 95 primary gliomas (37 grade II, 37 grade III, and 21 grade IV). We measured the tumor/normal brain uptake ratio (T/N ratio) on each PET and investigated the correlations among the tracer uptake, tumor grade, tumor type, and tumor proliferation activity. In addition, we compared the ease of visual evaluation for tumor detection. All 3 of the tracers showed positive correlations with astrocytic tumor (AT) grades (II/IV and III/IV). The MET T/N ratio of oligodendroglial tumors (OTs) was significantly higher than that of ATs of the same grade. The CHO T/N ratio showed a significant positive correlation with histopathologic grade in OTs. Tumor grade and type influenced MET uptake only. MET T/N ratios of more than 2.0 were seen in 87% of all of the gliomas. All of the tracers showed significantly positive correlations with Mib-1 labeling index in ATs but not in OTs and oligoastrocytic tumors. MET PET appears to be useful in evaluating grade, type, and proliferative activity of ATs. CHO PET may be useful in evaluating the potential malignancy of OTs. In terms of visual evaluation of tumor localization, MET PET is superior to FDG and CHO PET in all of the gliomas, due to its straightforward detection of "hot lesions".

Chemometric Studies on Brain-uptake of PET Agents via VolSurf Analysis

High initial (2 minutes after iv injection) brain-uptake of PET agents is required to deliver the agent to binding sites in brain tissue but, for quantification of the specific binding, relatively rapid washout of free and non-specifically bound PET agents from the brain (30 minutes after injection) also is required. In order to compare the physicochemical properties of the PET agents which are responsible for early brain-uptake and rapid washout, respectively, chemometric analysis on brain-uptake of PET agents was performed via a classical VolSurf approach. According to the PCA and PLS results, high 2-30 min brain-uptake ratio seems to be related to the large hydrophobic regions in the PET agents which are not confined to a particular surface.

Comparison of18F-fluoromethylcholine and 2-deoxy-D-glucose in the distribution of tumor and inflammation

The distribution characteristics of 18F-fluoromethylcholine (18F-choline) in tumor and inflammatory tissue were compared with those of 14C or 3H-2-deoxyglucose (2DG) as a substitute for fluorodeoxyglucose (FDG). A solid tumor model of AH 109A in the back of Donryu rats and an aseptic inflammation model of turpentine oil injection subcutaneously in rats were used for experiments. Tissue distribution was examined at 5, 30 and 60 min after injection of a mixture of 18F-choline and 3H-2DG. Double-tracer high-resolution autoradiographs (ARGs) of tumor and inflammation were obtained using 18F-choline and 14C-2DG. Whole body (WB) ARG was performed with 18F-choline. Tumor uptake of 18F-choline reached a peak at 30 min, when the tumor to blood ratio was 5.1. Both tumor and inflammation uptake of 2DG were higher than those of 18F-choline. 18F-choline uptake by inflammation was lower than that by tumor. The tumor to brain uptake ratio was 5.7 with 18F-choline and 1.2 with 2DG. In the ARG of inflammation, linear or ring-like structures of 2DG uptake were observed in the wall of the abscess, but were not identified with 18F-choline. Photomicrography showed that the uptake was limited to granulocytes, macrophages and fibroblasts, consistent with sub-acute or chronic inflammation. 18F-choline uptake by inflammation was lower than that of 2DG in the tissue distribution study, and 18F-choline uptake by abscess wall was significantly lower than that of 2DG in the autoradiography study. Our results may suggest the feasibility of 18F-choline-PET imaging for the differential diagnosis of cancer and chronic inflammation in lung and brain.

New method for improved reproducibility of ROI position in aorta, and automation of gamma fitting in BUR examination for non-invasive cerebral blood flow measurement

The brain uptake ratio (BUR) is useful for non-invasive cerebral blood flow measurements. To obtain this ratio requires setting an ROI on the aorta to draw the time-activity curve (TAC). Previously, the ROI has been manually set, in order to avoid two undesirable positionings: 1) protrusion from the aorta and 2) overlap in a vein or lung. However, these manual methods are affected by operator subjectivity, which results in individual variations in TAC. In calculating the area under the curve (AUC), gamma fitting of TAC is also affected by operator subjectivity. These subjective operations are considered to be an important impediment to the reproducibility of AUC. Better reproducibility of AUC would lead to improved measurement of brain perfusion. In this study, two newly devised trials were undertaken: 1) defining a system for setting ROI on the aorta; 2) and automatic gamma fitting for TAC. As a result of these trials, the individual variation in AUC among operators decreased, and the reproducibility of AUC was enhanced.

Positron emission tomography with injection of methionine as a prognostic factor in glioma.

Positron emission tomography with L-[methyl-11C]methionine (MET-PET) provides information on the metabolism of gliomas. The aim of this study was to determine the predictive value of MET-PET in the treatment of patients with gliomas. Since 1992, 85 patients with a World Health Organization (WHO) classification-verified glioma underwent PET studies in which MET was injected before (74 cases) or after treatment (11 cases). Analysis of PET data was conducted by the same investigator using two scales: a qualitative visual grading scale and a quantitative scale (ratio between tumor uptake and normal brain uptake, classified on a seven-level scale). Uptake of MET was present in 98% of gliomas. The investigator judged this uptake to be moderate to very high based on visual inspection (qualitative scale). For all grades of gliomas, a visual grade of 3 was statistically associated with a shorter patient survival period (p < 0.005). The tumor/normal brain uptake ratio was significantly influenced by the histological grade of the tumor. A statistically poor outcome was demonstrated when this ratio was higher than a threshold of 2.2 for a WHO Grade II tumor and 2.8 for WHO Grade III tumor. For Grade II and III tumors, oligodendrogliomas had a higher uptake of MET than astrocytomas. Uptake of MET was present in 98% of the gliomas studied. A high uptake is statistically associated with a poor survival time. The intensity of MET uptake represents a prognostic factor for WHO Grade II and III tumors considered separately.

Brain tumors: detection with C-11 choline PET.

To evaluate the effectiveness of positron emission tomography (PET) with carbon-11 choline in brain tumor imaging. A rat glioma cell line (C6) was incubated with C-14 choline; the time course of uptake and metabolism was determined in vitro. C-11 choline was injected intravenously in tumor-bearing rats; the time course of distribution in organs was determined. C-11 choline also was injected intravenously in 20 patients (aged 6-86 years) with brain tumors and two volunteers (aged 38 and 58 years); distribution of the tracer in the brain was determined. Regional cerebral blood flow was measured by using oxygen-15 water on the same day. C-14 choline was metabolized to phosphoryl choline in glioma cells. The uptake of C-11 choline by glioblastoma cells was three to four times higher than that in the rat brain. All brain tumors took up more C-11 choline than did normal brain; thus, brain tumors that were not treated, as well as those that were treated with surgery or radiation therapy, were depicted. The tumor-normal brain uptake ratio of C-11 choline in brain tumor did not correlate with the O-15 water regional blood flow in the corresponding area. C-11 choline PET can depict brain tumors effectively. This method was clinically useful in patients who had undergone surgery.

Synthesis and characterization of technetium-99m-labeled tropanes as dopamine transporter-imaging agents.

In the development of novel Tc-99m-labeled tropane derivatives as dopamine transporter (reuptake site)-imaging agents, a series of neutral and lipophilic complexes containing bis-(aminoethanethiol) as a neutral complexing moiety for a [99mTc]TcO3+ center core was successfully prepared. Biological evaluation of the Tc-99m-labeled complexes 13-16 as central nervous system (CNS) dopamine transporter-imaging agents was reported. Synthesis of the tropane derivatives was achieved by stepwise reactions adding two aminoethanethiol units. The final free thiol ligands were obtained by deblocking the 4-methoxybenzyl protecting group with Hg(OAc)2 to obtain trifluoroacetate salts. All of the Tc-99m complexes, with the exception of 16, displayed good initial brain uptake and selective uptake in the striatal area, where dopamine transporters are concentrated. One of the compounds, [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo [3.2.1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethy] amino]ethanethiolato-(3-)-N2,N2',S2,S2'] oxo-[1R-(exo-exo)]- [99mTc]technetium,[99mTc]TRODAT-1 (13), displayed the highest initial uptake in rat brain (0.4% at 2 min post iv injection); the striatal/cerebellar (ST/ CB) ratio reached 2.8 at 60 min after an iv injection. The specific uptake in rat brain can be blocked by pretreating rats with a competing dopamine transporter binding agent, beta-CIT (RTI-55, 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane; iv, 1 mg/kg), which reduced the regional brain uptake ratio (ST/CB) to 1.2. In contrast, the specific striatal uptake was not affected by pretreating rats with a noncompeting ligand, haldol (iv, 1 mg/kg). After an iv injection of 9 mCi of [99mTc]TRODAT-1 (13), in vivo images of baboon brain using single-photon emission-computed tomography exhibited excellent localization in striatum (basal ganglia), where dopamine neurons are known to be concentrated. This series of compounds may provide a convenient source of short-lived imaging agents for routine diagnosis of CNS diseases (i.e., Parkinson's disease) in which changes in the dopamine transporter concentration are implicated.

Tc-99m-labeled tropanes as dopamine transporter imaging agents.

The development of novel Tc-9m-labeled tropane derivatives as dopamine transporter imaging agents is reported. A series of neutral and lipophilic conjugated complexes, containing N-(alkylthiolato)-tropane, aminobis(ethylthiolato), and a [99mTc]TcO3+ center core, were prepared and evaluated as central nervous system (CNS) dopamine transporter imaging agents in rats. One of the compounds, [99mTC]technetium, [methyl 3-(4-chlorophenyl)-8-(2-mercaptoethyl-8-azabicyclo [3.2.1]octane-2-carboxylato-S][[2,2'-(methylimino)bis[eth anethiolato]] (2-)-N,S,S']oxo (25), displayed low initial uptake in rat brain (0.1% at 2 min post i.v. injection); the striatal/cerebellar (ST/CB) ratio reached 3.50 at 60 min after an i.v. injection. The specific uptake can be blocked by pretreating rats with a competing dopamine transporter binding agent, beta-CIT (RTI-55, N-methyl-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane; i.v. 1 mg/kg), which reduced the regional brain uptake ratio (ST/CB) to 1.0. In contrast, the specific uptake in striatum was not affected by pretreating rats with a noncompeting ligand, haldol (i.v., 1 mg/kg). In vitro autoradiography of rat brain sections exhibited elevated labeling in striatum, major islands of Calleja, and olfactory tubercle regions, where dopamine neurons are known to be concentrated. This series of compounds is the first example of technetium-99m labeled CNS receptor-specific imaging agents and may provide a convenient source of short-lived imaging agents for routine diagnosis of CNS abnormality in conjunction with single photon emission computed tomography.

Structure-activity relationships of 123I labeled o-iodobenzamide derivatives

o-Iodobenzamide is a stable compound which is labeled quantitatively by heating with no-carrier-added123I-NaI in ethanol. The123I product is relatively inert biologically, being resistant toin vivo deiodination or hydrolysis, in rats and dogs, for several hours. Furthermore, it appears to be freely diffusible, distributing itself in the body according to the extravascular fluid space, with some localization in the liver, and little tendency for excretion into the urine or bile. The brain uptake and brain-blood ratio is higher than that of iodoantipyrine, and allows imaging the brain in dogs. The product is also taken up by induced myocardial infarcts and transplanted tumors in rats. Substitution of the amide function with single alkyl groups does not greatly alter thein vivo characteristics except at long-chain length where hepatobiliary excretion predominates. Substitution of both amide hydrogens, however, results in a different pattern, with high blood binding and increased excretion. Conversion to more polar functionalities, such as the hydrazide or hydroxamic acid, also leads to hepatobiliary excretion.

Blood-brain transport of tryptophan and phenylalanine: effect of portacaval shunt in dogs.

The blood-brain uptake process for tryptophan and phenylalanine was investigated using the multiple-indicator dilution technique in 13 unanesthetized dogs with and without portacaval shunts. Tracer doses of labeled albumin (extracellular reference) and tryptophan or phenylalanine, prepared in autologous dog plasma, were injected into one carotid artery, and dorsal sagittal sinus dilution curves were obtained. Portacaval shunting was not associated with significant changes in the initial brain uptake ratio U for tryptophan or phenylalanine, despite increases in plasma phenylalanine and tyrosine. In the 13 dogs, U was not significantly correlated with the plasma levels of either the different branched-chain or aromatic amino acids or the molar ratio between these groups. These findings do not support the current hypothesis that the active transport of aromatic amino acids across the blood-brain barrier is increased after portacaval shunt. Our data suggest, instead, that the blood-brain uptake process for aromatic amino acids is linear and increases in shunted animals because their plasma levels are increased.

Structure-activity relationships of123I labeled o-iodobenzamide derivatives

Abstract o-Iodobenzamide is a stable compound which is labeled quantitatively by heating with no-carrier-added123I-NaI in ethanol. The123I product is relatively inert biologically, being resistant toin vivo deiodination or hydrolysis, in rats and dogs, for several hours. Furthermore, it appears to be freely diffusible, distributing itself in the body according to the extravascular fluid space, with some localization in the liver, and little tendency for excretion into the urine or bile. The brain uptake and brain-blood ratio is higher than that of iodoantipyrine, and allows imaging the brain in dogs. The product is also taken up by induced myocardial infarcts and transplanted tumors in rats. Substitution of the amide function with single alkyl groups does not greatly alter thein vivo characteristics except at long-chain length where hepatobiliary excretion predominates. Substitution of both amide hydrogens, however, results in a different pattern, with high blood binding and increased excretion. Conversi...

Lysine metabolism in the rat brain: blood-brain barrier transport, formation of pipecolic acid and human hyperpipecolatemia.

Abstract—Through the use of intravenous pulse injection of L‐[U‐14C] lysine, the blood‐brain barrier transport of L‐lysine was studied. The uptake of L‐lysine plus metabolites in the brain remained essentially unchanged at approx 0.002–0.005 nmol/g in the low dose (3μg per kg body weight) injection, and 20–40 nmol/g in the high dose (30 mg/kg) injection throughout the time intervals of up to 60 min. The uptake of L‐lysine plus metabolites in the heart, however, decreased substantially from 0.03 to 0.003 nmol/g in the low dose injection and from 320 to 62 nmol/g in the high dose injection. The plasma to heart uptake ratio only decreased slightly through the 60 min period: from 6 to 2 in either the low or high dose L‐lysine injection. The plasma to brain uptake ratio, however, decreased rapidly from a high of 62 to a low of about 4 in either the low or high dose injection throughout the 60‐min time course. Study of labeled L‐pipecolate formation in the plasma and individual organs indicates that this compound was formed only in the brain to a significant level within 0.5 min of 14C‐L‐lysine intravenous pulse injection. Labeled pipecolate was recovered from heart, liver, kidney and plasma in significant quantities only at 2 min or later after pulse‐injection. It is concluded that the blood‐brain barrier of L‐lysine in the rat is not particularly strong and that the rat brain may be primarily responsible for L‐pipecolate synthesis from L‐lysine. The possible etiology of human hyperpipecolatemia is also discussed in light of the current findings.

Uptake of 51Cr-beta-glycerophosphate by experimental brain tumor.

A new radioactive compound the 51Cr-β-glycerophosphate complex, which accumulates in different types of tumor, has been assayed in mice transplanted subcutaneously with brain tumor. A very high tumor to brain uptake ratio was observed throughout the experiment (72 h). The optimal interval seemed to be between 6 and 24 h. The biochemical mechanism involved in the accumulation of the compound by the Tumor appeared to be more complex than a simple phosphomonoesterase action.