Comparison of brain serotonin transporter using [I-123]-ADAM between obese and non-obese young adults without an eating disorder.

Cerebral serotonin metabolism has an important but controversial role in obesity. However, it is not given enough attention in morbidly obese young adults. We used single photon emission computed tomography (SPECT) with [I-123]-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM) to investigate changes in serotonin transporter (SERT) availability in 10 morbidly obese young adults without an eating disorder (M/F = 5/5, body mass index (BMI): 40.3 ± 4.1 kg/m2, percentage of body fat (BF%): 46.0 ± 3.9%) and 10 age- and sex-matched non-obese controls (BMI: 20.3 ± 1.2 kg/m2, BF%: 20.6 ± 8.9%). All participants underwent SPECT at 10 min and 6 h after an injection of 200 MBq of [I-123]-ADAM. The SERT binding site (midbrain) was drawn with cerebellum normalization. The BF% and fat distribution were measured using dual-energy X-ray absorptiometry. The midbrain/cerebellum SERT binding ratios (2.49 ± 0.46 vs. 2.47 ± 0.47; p = 0.912) at 6 h were not significantly different between groups, nor was the distribution of the summed images at 10 min (1.36 ± 0.14 vs. 1.35 ± 0.11; p = 0.853). There were no significant correlations between midbrain/cerebellum SERT binding ratio and age, BMI, BF%, or fat distribution. No significant difference in SERT availability in the midbrain between morbidly obese and non-obese young adults without an eating disorder indicates an unmet need for investigating the role of cerebral serotonin in obesity.

Association study of serotonin transporter availability and SLC6A4 gene polymorphisms in patients with major depression.

The serotonin transporter (SERT) is hypothesized to be an important component of the pathophysiology of major depression (MD). The aim of this study was to use [(123)I]ADAM single-photon emission computed tomography (SPECT) to explore whether SERT availability in four regions of the brain (striatum, thalamus, midbrain and pons) is different in patients with MD and healthy individuals. The effects of three genetic variants (rs25531, rs6354 and STin2) of the serotonin transporter gene (SLC6A4) on SERT availability were also investigated. This study included 40 MD patients and 12 controls. The mean specific uptake ratio (SUR) values in the thalamus differed significantly between MD patients and controls. Genetic variants of SLC6A4, age, gender, severity of depression, and smoking behavior did not influence SERT availability. SERT availability might be a useful biomarker of the development of MD; however, a larger sample size is needed to provide more concrete evidence.

Characterization of neuroblastic tumors using 18F-FDOPA PET.

UNLABELLED: Neuroblastic tumors are childhood neoplasms that possess amino acid decarboxylase (AADC) activity and can theoretically be imaged by (18)F-fluorodihydroxyphenylalanine ((18)F-FDOPA) PET, a new diagnostic tool for neuroendocrine tumors. In this study, we explored the accuracy and clinical role of (18)F-FDOPA PET in neuroblastic tumors. METHODS: From 2008 to 2011, patients with tissue-proven neuroblastic tumors receiving (18)F-FDOPA PET at initial diagnosis or during follow-ups were enrolled. The sensitivity and specificity of (18)F-FDOPA PET were compared with those of (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy and (18)F-FDG PET, using tumor histology as the standard. The maximum standardized uptake value and tumor-to-liver uptake ratio on (18)F-FDOPA PET were measured and correlated with AADC messenger RNA level in tumor tissue. RESULTS: Fifty tumors from 34 patients, including 42 neuroblastic tumors and 8 lesions without viable tumor cells, were eligible for analysis. (18)F-FDOPA PET successfully detected neuroblastic tumors of different histologic types in various anatomic sites, at a sensitivity of 97.6% (87.4%-99.9%) and a specificity of 87.5% (47.3%-99.7%). In tumors with concomitant studies, (18)F-FDOPA PET demonstrated a higher sensitivity than (123)I-MIBG scintigraphy (n = 18; P = 0.0455) or (18)F-FDG PET (n = 46; P = 0.0455). Among the 18 tumors with concomitant (123)I-MIBG scans, 4 tumors with viable cells were (123)I-MIBG-negative but were successfully detected by (18)F-FDOPA PET. The tumor uptake of (18)F-FDOPA significantly correlated with AADC expression (n = 15 nonhepatic tumors; maximum standardized uptake value, P = 0.0002; tumor-to-liver uptake ratio, P < 0.0001). CONCLUSION: (18)F-FDOPA PET showed high sensitivity and specificity in detecting and tracking neuroblastic tumors in this preliminary study with a small cohort of patients and might be complementary to (123)I-MIBG scintigraphy and (18)F-FDG PET. By correlating with AADC expression, (18)F-FDOPA PET might serve as a useful imaging tool for the functional assessment of neuroblastic tumors.

Tc-99m-HL91 imaging in the early detection of neuronal injury in a neonatal rat model of hypoxic ischemia.

OBJECTIVE: Hypoxic-ischemic insult in newborns results in progressive neuronal loss. For neuroprotective therapy to be effective, it is important to identify high-risk neonates soon after birth. 99mTc-labeled imaging agent, Tc-99m-HL91, developed as a putative hypoxic reagent, has been reported to demonstrate increased uptake in ischemic myocardium. We hypothesized that Tc-99m-HL91 is sensitive for the early identification of hypoxic-ischemic injury in neonatal rat brains. DESIGN: Laboratory investigation. SETTING: University research laboratory. SUBJECTS: Sprague-Dawley rat pups. INTERVENTIONS: Postnatal day-7 pups were divided into four groups: hypoxic-ischemia, hypoxia-only, ischemia-only, and controls. In the early (2 hrs), intermediate (20 hrs), and late (44 hrs) reoxygenation phases, Tc-99m-HL91 in vivo and ex vivo imaging and quantitative autoradiography were performed. Regions of interest were drawn to calculate the contrast ratio of Tc-99m-HL91 uptake between the ipsilateral and contralateral hemispheres. Pathology, cerebral blood flow, and blood-brain barrier damage were determined. MEASUREMENTS AND MAIN RESULTS: After hypoxic-ischemia, there were very few pyknotic neurons in the early phase, many pyknotic neurons in the intermediate phase, and extensive neuronal loss in the late phase postreoxygenation. Blood-brain barrier damage occurred in the early phase, progressed in the intermediate phase, and became extensive in the late phase. The hypoxia-only and ischemia-only pups showed no neuronal or blood-brain barrier damage and had higher cerebral blood flow postreoxygenation compared with the hypoxia-ischemia pups. Regions of interest analysis of in vivo and ex vivo images and autoradiography revealed significantly higher Tc-99m-HL91 contrast ratio at early and intermediate phases, not late phase of hypoxic-ischemic group. Hypoxic-ischemia group had significantly higher contrast ratio values in the early and intermediate phases than the hypoxia-only and ischemia-only groups. A contrast ratio value of 0.15 in the early phase on postnatal day 7 had a sensitivity of 0.95 and specificity of 0.89 in detecting significant hypoxic-ischemic lesions on postnatal day 21. CONCLUSION: Tc-99m-HL91 uptake is sensitive for the early detection of hypoxic-ischemic injury in neonatal brains.

Recent advances in imaging of dopaminergic neurons for evaluation of neuropsychiatric disorders.

Dopamine is the most intensely studied monoaminergic neurotransmitter. Dopaminergic neurotransmission plays an important role in regulating several aspects of basic brain function, including motor, behavior, motivation, and working memory. To date, there are numerous positron emission tomography (PET) and single photon emission computed tomography (SPECT) radiotracers available for targeting different steps in the process of dopaminergic neurotransmission, which permits us to quantify dopaminergic activity in the living human brain. Degeneration of the nigrostriatal dopamine system causes Parkinson's disease (PD) and related Parkinsonism. Dopamine is the neurotransmitter that has been classically associated with the reinforcing effects of drug abuse. Abnormalities within the dopamine system in the brain are involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Dopamine receptors play an important role in schizophrenia and the effect of neuroleptics is through blockage of dopamine D(2) receptors. This review will concentrate on the radiotracers that have been developed for imaging dopaminergic neurons, describe the clinical aspects in the assessment of neuropsychiatric disorders, and suggest future directions in the diagnosis and management of such disorders.

Involvement of SHP2 in focal adhesion, migration and differentiation of neural stem cells.

OBJECTIVES: SHP2 (Src-homology-2 domain-containing protein tyrosine phosphatase) plays an important role in cell adhesion, migration and cell signaling. However, its role in focal adhesion, differentiation and migration of neural stem cells is still unclear. METHODS: In this study, rat neurospheres were cultured in suspension and differentiated neural stem cells were cultured on collagen-coated surfaces. RESULTS: The results showed that p-SHP2 co-localized with focal adhesion kinase (FAK) and paxillin in neurospheres and in differentiated neural precursor cells, astrocytes, neurons, and oligodendrocytes. Suppression of SHP2 activity by PTP4 or siRNA-mediated SHP2 silencing caused reduction in the cell migration and neurite outgrowth, and thinning of glial cell processes. Differentiation-induced activation of FAK, Src, paxillin, ERK1/2, and RhoA was decreased by SHP2 inactivation. CONCLUSIONS: These results indicate that SHP2 is recruited in focal adhesions of neural stem cells and regulates focal adhesion formation. SHP2-mediated regulation of neural differentiation and migration may be related to formation of focal adhesions and RhoA and ERK1/2 activation.

Direct determination of ECD in ECD Kit: a solid sample quantitation method for active pharmaceutical ingredient in drug product.

Technetium-99m ethyl cysteinate dimer (Tc-99m-ECD) is an essential imaging agent used in evaluating the regional cerebral blood flow in patients with cerebrovascular diseases. Determination of active pharmaceutical ingredient, that is, L-Cysteine, N, N'-1,2-ethanediylbis-, diethyl ester, dihydrochloride (ECD) in ECD Kit is a relevant requirement for the pharmaceutical quality control in processes of mass fabrication. We here presented a direct solid sample determination method of ECD in ECD Kit without sample dissolution to avoid the rapid degradation of ECD. An elemental analyzer equipped with a nondispersive infrared detector and a calibration curve of coal standard was used for the quantitation of sulfur in ECD Kit. No significant matrix effect was found. The peak area of coal standard against the amount of sulfur was linear over the range of 0.03-0.10 mg, with a correlation coefficient (r) of 0.9993. Method validation parameters were achieved to demonstrate the potential of this method.

Molecular imaging, pharmacokinetics, and dosimetry of In-AMBA in human prostate tumor-bearing mice.

Molecular imaging with promise of personalized medicine can provide patient-specific information noninvasively, thus enabling treatment to be tailored to the specific biological attributes of both the disease and the patient. This study was to investigate the characterization of DO3A-CH(2)CO-G-4-aminobenzoyl-Q-W-A-V-G-H-L-M-NH(2) (AMBA) in vitro, MicroSPECT/CT imaging, and biological activities of (111)In-AMBA in PC-3 prostate tumor-bearing SCID mice. The uptake of (111)In-AMBA reached highest with 3.87 ± 0.65% ID/g at 8 h. MicroSPECT/CT imaging studies suggested that the uptake of (111)In-AMBA was clearly visualized between 8 and 48 h postinjection. The distribution half-life (t(1/2α)) and the elimination half-life (t(1/2ß)) of (111)In-AMBA in mice were 1.53 h and 30.7 h, respectively. The C(max) and AUC of (111)In-AMBA were 7.57% ID/g and 66.39 h % ID/g, respectively. The effective dose appeared to be 0.11 mSv/MBq(-1). We demonstrated a good uptake of (111)In-AMBA in the GRPR-overexpressed PC-3 tumor-bearing SCID mice. (111)In-AMBA is a safe, potential molecular image-guided diagnostic agent for human GRPR-positive tumors, ranging from simple and straightforward biodistribution studies to improve the efficacy of combined modality anticancer therapy.

Development and validation of an anion-exchange HPLC method for the determination of fluoride content and radiochemical purity in [18F]NaF.

(18)F-labeled sodium fluoride ([(18)F]NaF) is a useful bone imaging agent that has been demonstrated to be significantly more accurate than (99m)Tc-labeled methylene diphosphonate for the detection of both sclerotic and lytic lesions in various malignancies. A reliable anion-exchange HPLC method equipped with suppressed conductivity and radioactive detectors has been developed in order to analyze the content of NaF and radiochemical purity in [(18)F]NaF radiopharmaceuticals. The method described for fluoride analysis uses an isocratic elution of NaF in a Hamilton anion-exchange column using a mobile phase that consists of 7.5 mM sodium carbonate and 0.018 mM potassium thiocyanate. The flow rate was 1.0 ml/min. The method was validated in accordance with several parameters, including system suitability, specificity, precision, accuracy, linearity, robustness, limit of detection and limit of quantification. The results are described as follows: (1) The system suitability includes the tailing factor, theoretical plate number and resolution, which are 1.192534, 2729.6594 and 16.7415, respectively. (2) For specificity, the solvent peak and chloride ion did not interfere with the retention time of the fluoride. (3) The percentage coefficient of variation for analysis of precision, including repeatability and intermediate precision, is less than 2.0%. (4) Accuracy of method is within the range of 98%-102%. (5) The range of linearity is from 10 to 400 µg/ml, with the correlation coefficient (R(2)) always being above 0.9985. (6) The data of method robustness are within acceptance criteria. (7) The limit of detection and limit of quantification are 0.0678 and 0.20 µg/ml, respectively. All of the analysis results demonstrate that this method is highly sensitive, convenient, specific and suitable for quantification of NaF over a wide linear range. Therefore, the method can be successfully performed for routine analysis of fluoride content in [(18)F]NaF radiopharmaceuticals and reduce the time required for analysis.

The role of molecular imaging in the diagnosis and management of neuropsychiatric disorders.

Neuropsychiatric disorders are becoming a major socioeconomic burden to modern society. In recent years, a dramatic expansion of tools has facilitated the study of the molecular basis of neuropsychiatric disorders. Molecular imaging has enabled the noninvasive characterization and quantification of biological processes at the cellular, tissue, and organism levels in intact living subjects. This technology has revolutionized the practice of medicine and has become critical to quality health care. New advances in research on molecular imaging hold promise for personalized medicine in neuropsychiatric disorders, with adjusted therapeutic doses, predictable responses, reduced adverse drug reactions, early diagnosis, and personal health planning. In this paper, we discuss the development of radiotracers for imaging dopaminergic, serotonergic, and noradrenergic systems and ß-amyloid plaques. We will underline the role of molecular imaging technologies in various neuropsychiatric disorders, describe their unique strengths and limitations, and suggest future directions in the diagnosis and management of neuropsychiatric disorders.

The biological characterization of (99m)Tc-BnAO-NI as a SPECT probe for imaging hypoxia in a sarcoma-bearing mouse model.

OBJECTIVES: Tumor growth beyond the region where vascular oxygen can reach creates a hypoxic domain. In this study, BnAO, a ligand that had been labeled with (99m)Tc-pertechnetate for hypoxia imaging, was conjugated with 2-nitroimidazole to give 3,3,10,10-tetramethyl-1-(2-nitro-1H-imidazo-1-y1)-4,9-diazadodecane-2,11- dionedioxime (BnAO-NI) as a potential ligand for hypoxia detection. Pentoxifylline is a peripheral vasodilator and has been used as a radiosensitizer in tumor radiotherapy. (99m)Tc-BnAO-NI/SPECT was applied to noninvasively assess the pharmacological effect of pentoxifylline in reducing tumor hypoxia in vivo. METHODS: BnAO-NI was synthesized and formulated with methylene diphosphonate (MDP), stannous chloride and carbonate buffer to afford kits. After mixing with (99m)Tc-pertechnetate, (99m)Tc-BnAO-NI injection can be readily prepared. The partition coefficient, radiochemical purity and in vitro stability were determined. Cellular uptake of radiotracers in KHT cells under hypoxia was conducted in a CO(2) incubator at 37°C under hypoxia or normoxia. A biodistribution study after intravenous injection of (99m)Tc-BnAO-NI in KHT sarcoma-implanted C3H mice was performed. The effect of pentoxifylline (100 mg/kg) on reducing tumor hypoxia was also studied. RESULTS: The radiochemical purity (RCP) of the (99m)Tc-BnAO-NI preparation was greater than 96% and stable at ambient temperature for 24h (RCP>90%). The accumulation of (99m)Tc-BnAO-NI and (99m)Tc-BnAO in KHT cells under hypoxia were 3.57 and 4.13-fold higher than those under normoxic environment, indicating unambiguous oxygen-dependent uptakes of these two probes. The distribution of (99m)Tc-BnAO-NI in KHT sarcoma-bearing mice revealed rapid clearance from the blood circulation. The tumor uptake peaked at 2h post-injection (0.32 ± 0.05%ID/g) with tumor-to-blood and tumor-to-muscle ratios of 10.32 and 3.96, respectively. The effect of pentoxifylline on the tumor blood perfusion was obvious. The tumor-to-muscle ratios at 2h post-injection of (99m)Tc-BnAO-NI with and without pentoxifylline pretreatment were 1.67 ± 0.38 and 2.59 ± 0.25, respectively (p = 0.025, n = 3). CONCLUSION: This study demonstrates that (99m)Tc-BnAO-NI is a hypoxia-sensitive radio probe for monitoring hypoxic regions in a malignant neoplasm. However, (99m)Tc-BnAO-NI, though with higher lipophilicity than (99m)Tc-BnAO, did not achieve better specific accumulation in hypoxic tissues. (99m)Tc-BnAO-NI/SPECT could be applied in clinics to noninvasively evaluate the feasibility of using pentoxifylline as a radiosensitizer by reducing tumor hypoxia in vivo.

Monitoring of 2-deoxy-2-[18F]fluoro-D-glucose uptake in tumor-bearing mice using high-sensitivity projection imaging: compared with PET imaging.

OBJECTIVE: To investigate the feasibility of using high-sensitivity projection [F]fluoro-deoxyglucose imaging to monitor chemotherapeutic efficacy in BALB/c mice bearing CT-26 tumor implants. METHODS: A planar positron imaging system (PPIS)-4800 and a microPET R4 were used for projection and tomographic imaging, respectively. Six disks filled with different volumes of F-FDG solution were scanned by PPIS for calibration check. Tumor-bearing mice were treated with saline (control) or cyclophosphamide by intraperitoneal injections. Tumor responses were evaluated by both PPIS and microPET imaging. RESULTS: The disk-activity ratios obtained from PPIS were 1.00: 1.30: 1.98: 2.48: 2.73: 3.53 with corresponding volume ratios of 1.0: 1.5: 2.0: 2.5: 3.0: 3.5. PPIS imaging in tumor-bearing mice showed that the tumor/non-tumor ratios were 1.62, 2.12, 3.03, 4.46, and 3.61 on days 7, 10, 13, 17, and 20, respectively, after tumor inoculation. In addition, PPIS was used to monitor the chemotherapeutic effect of cyclophosphamide on tumor-bearing mice. The correlation coefficients between the tumor sizes and tumor/non-tumor ratios for microPET and PPIS were 0.63 and 0.72, respectively, in the control group, and were 0.98 and 0.81, respectively, in the cyclophosphamide-treated group. CONCLUSION: This study showed that PPIS imaging is a feasible modality for monitoring tumor responses. These results suggest that PPIS, a potential high-throughput screening imaging system, may be used for the preclinical evaluation of tumor response to new anticancer drugs using murine tumor models.

Preliminary studies of differential impairments of the dopaminergic system in subtypes of progressive supranuclear palsy.

BACKGROUND: Richardson's syndrome (RS) and progressive supranuclear palsy-parkinsonism (PSP-P) are the most common subtypes of PSP syndrome. The clinical features, responses to levodopa, and progression are relatively different but overlap. Determining whether combined molecular imaging studies of dopamine transporter and D2 receptor are helpful for further differentiation of these two subtypes is important. METHODS: Ten patients with PSP (six suffering from RS and four from PSP-P) were studied. We also enrolled 10 patients with Parkinson's disease (PD) as disease control and seven healthy individuals as normal controls. Each individual underwent two sets of single photon emission computer tomography imaging, [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)-N2,N2',S2,S2']oxo[1R-(exo-exo)])-[Tc] Technetium (Tc-TRODAT-1) dopamine transporter (DAT) and I-iodobenzamide D2 receptor. The specific uptake ratio was calculated as (basal ganglia counts-occipital cortex counts)/occipital cortex counts. RESULTS: In DAT scan, the mean striatal uptake was reduced in the RS group compared with that in the PSP-P group, although it did not reach statistical significance. The putamen-to-caudate nucleus ratios were significantly different between PD and all PSP patients (P<0.001), but no difference in putamen-to-caudate ratios was found between the RS and PSP-P groups. In the I iodobenzamide scan, striatal uptake was significantly reduced in the RS group (-22.62%, P=0.022); on the contrary, it was mildly increased in the PSP-P group. CONCLUSION: The studies showed different alterations of DAT and D2 receptor function between the RS and PSP-P groups. Different DAT imaging might be helpful to distinguish PSP-P from PD in the early stage.

Development of acute and subacute toxicity with the serotonin transporter radiopharmaceutical, ADAM.

It is predicted that depression will become the most common neurological disease in the new millennium. Its incidence is currently about 3% of diseases worldwide. Serotonin is an essential neurotransmitter for the central and peripheral nervous systems and plays a crucial role in neuropsychiatric disorders. (123)I-labeled ADAM was developed to facilitate an early diagnosis of serotonin transporter (SERT) abnormalities in the brain. Many studies have confirmed that the binding of this radiotracer to SERTs is associated with depression. The aim of this study was to evaluate the acute and subacute toxicity of ADAM and to determine its no observed adverse effect level (NOAEL) by administering it via intravenous injection to Sprague-Dawley rats for 14 consecutive days. None of the animals died, and no treatment-related clinical signs were observed. Urinalysis, hematology, and clinical chemistry analysis revealed that daily administration of ADAM (2-2-dimethylaminomethylphenylthio-5-iodophenylamine) for 2 weeks had no toxicological effects. It is concluded that ADAM exerts no adverse toxic effects on this animal model. The NOAEL was 155 microg/kg/day.

The preparation and biological characterization of a new HL91-derivative for hypoxic imaging on stroke mice.

AIM: (99m)Tc-HL91 (Prognox, GE-Healthcare) was the first nonnitro-aryl-based radiotracer for evaluating hypoxic fraction in neoplasm, stroke and myocardium infarction regions. However, the high hydrophilicity of (99m)Tc-HL91 might hamper its penetration into cells. In this study, we prepared a new ligand 4,4,11,11-tetramethyl- 5,10-diazatetradecane- 3,12-dionedioxime (HL91-ET) with higher lipophilicity but structurally similar compared with that of HL91. The chemical and biological characterizations of (99m)Tc-HL91-ET as a scintigraphic probe for hypoxia were performed with a stroke-bearing mouse model. MATERIALS AND METHODS: HL91-ET was synthesized and formulated with stannous chloride and buffer to afford kits. After mixing with (99m)Tc-pertechnetate, (99m)Tc-HL91-ET can be prepared in high yield and high radiochemical purity (both >96%). The partition coefficient of (99m)Tc-HL91-ET was determined in n-octanol/PBS system. Cellular uptake assays under normoxic and hypoxic conditions were performed in an oxygen-controlled CO(2) incubator. Brain stroke in the mouse model was induced by the electrocautery of the middle cerebral artery. After intravenous injection of (99m)Tc-HL91-ET into the Balb/c mouse suffering brain stroke, small-animal SPECT images were acquired at designated time points and autoradiography of the brain slides was conducted. Parallel studies of (99m)Tc-HL91 were also conducted at the same conditions for comparison. RESULTS: The higher partition coefficient of (99m)Tc-HL91-ET (0.294+/-0.007) indicated higher lipophlicity compared with that of (99m)Tc-HL91 (0.089+/-0.005). The (99m)Tc-HL91-ET preparation was stable at ambient temperature for 24h. Cellular uptake assay showed that (99m)Tc-HL91-ET was less selectively retained in hypoxic cells than (99m)Tc-HL91. The target-to-normal brain ratios derived from the autoradiograms of the brains of stroke mice were 1.31+/-0.02 and 17.47+/-0.10 (n=3), respectively, at 2h post injection of (99m)Tc-HL91-ET and (99m)Tc-HL91. CONCLUSIONS: This study revealed that (99m)Tc-HL91-ET, though with higher lipophilicity than (99m)Tc-HL91, did not suggest better specific accumulation in hypoxic cells or tissues than (99m)Tc-HL91. The uptake mechanism of (99m)Tc-HL91 was at least not solely by passive diffusion. Lipophilicity should not be the major consideration in designing HL91-derivatives for hypoxia imaging.

Acute intravenous injection toxicity study of MIBG in mice.

Metaiodobenzylguanidine (MIBG) is an analog of norepinephrine. I-131-labeled MIBG has been thought to be safe and effective in the evaluation of neuroendocrine tumors, mainly in neuroblastoma and pheochromocytoma. This article describes the acute toxicity of MIBG in imprinting control region (ICR) mice. Treated mice were administered with MIBG at dose levels of 75, 150, and 300ng/kg with dose volumes of 20mL/kg. The control mice were administered 20mL/kg of vehicle control. The mice were observed for 14 days. Observations included general demeanor, clinical signs, mortality, body weights/total body-weight gains, and gross necropsy findings. None of the animals died during the 14-day study period. There was no difference in body weights among all treated and control mice.

Study on the neuroprotective effect of fluoxetine against MDMA-induced neurotoxicity on the serotonin transporter in rat brain using micro-PET.

3, 4-Methylenedioxymethamphetamine (MDMA, "ecstasy") has toxic effects on serotonergic neurons in the brain. Our aim was to determine whether N,N-dimethyl-2-(2-amino-4-[(18)F]-fluorophenylthio) benzylamine (4-[(18)F]-ADAM; a serotonin transporter imaging agent) and micropositron emission tomography (micro-PET) can be used to examine in vivo the effect of fluoxetine on MDMA-induced loss of serotonin transporters in rat brain. Male Sprague-Dawley rats were injected with fluoxetine [1 dose, 5 mg/kg, subcutaneously (s.c.)] followed by MDMA (twice a day for 4 consecutive days, 10 mg/kg, s.c.). Micro-PET with 4-[(18)F]-ADAM was performed on days 4, 10, 17, 24, and 31. In addition, the time course of occupancy by fluoxetine at 4-[(18)F]-ADAM sites was measured. Specific 4-[(18)F]-ADAM uptake ratios (SURs) were calculated from the micro-PET imaging data for various brain regions. Immunohistochemistry was performed 7 days after the last micro-PET scan. From day 4 to day 31, SURs were markedly decreased (by approximately 55-75% compared to control values) in all brain regions in MDMA-treated rats. The effect of MDMA was markedly attenuated (approximately 30-50%) by fluoxetine. The fluoxetine-induced decrease in uptake in different brain regions was 40-75% at 90-min postinjection, and this decrease returned to baseline values in most brain regions by day 31. The distribution and intensity of serotonin transporter (SERT) immunostaining in the brain paralleled the PET imaging results, suggesting that a single dose of fluoxetine provides long-lasting protection against MDMA-induced loss of SERT and that such neuroprotection is detectable in vivo by 4-[(18)F]-ADAM micro-PET.