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  • 1
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Organometallics 11 (1992), S. 122-127 
    ISSN: 1520-6041
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Journal of the American Chemical Society 117 (1995), S. 11037-11038 
    ISSN: 1520-5126
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Transition metal chemistry 23 (1998), S. 531-536 
    ISSN: 1572-901X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Technetium-99m (T1/2=6h, 140keV) is the most commonly used short-lived radionuclide for diagnostic nuclear medicine imaging. It is important from an inorganic chemistry point of view to develop novel ligands and chelation chemistry associated with this radionuclide, because many patients could potentially benefit from advances in technetium chemistry. Recent studies showed that formation of tropane derivatives containing a neutral [TcVO]3+N2S2 complex are useful as dopamine transporter imaging agents. These agents may be important for the imaging of patients with Parkinson's and other neurodegenerative diseases.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1619-7089
    Keywords: Key words: Striatum ; Single-photon emission tomography ; Dopamine neuron ; 6-OH-dopamine ; Autoradiography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Technetium-99m is the most commonly used radionuclide in routine nuclear medicine imaging procedures. Development of 99mTc-labeled receptor-specific imaging agents for studying the central nervous system is potentially useful for evaluation of brain function in normal and disease states. A novel 99mTc-labeled tropane derivative, [99mTc]TRODAT-1, which is useful as a potential CNS dopamine transporter imaging agent, was evaluated and characterized. After i.v. injection into rats, [99mTc]TRODAT-1 displayed specific brain uptake in the rat striatal region (striatum-cerebellum/cerebellum ratio 1.8 at 60 min), where dopamine neurons are concentrated. The specific striatal uptake could be blocked by pretreating rats with a dose of competing dopamine transporter ligand, β-CIT (or RTI-55, i.v., 1 mg/kg). However, the specific striatal uptake of [99mTc]TRODAT-1 was not affected by co-injection of excess free ligand (TRODAT-1, up to 200 μg per rat) or by pretreating the rats with haloperidol (i.v., 1 mg/kg). The specific uptake in striatal regions of rats that had prior 6-hydroxydopamine lesion in the substantia nigra area showed a dramatic reduction. The radioactive material recovered from the rat striatal homogenates at 60 min after i.v. injection of [99mTc]TRODAT-1 showed primarily the original compound (〉95%), a good indication of in vivo stability in brain tissue. Similar and comparable organ distribution patterns and brain regional uptakes of [99mTc]TRODAT-1 were obtained for male and female rats. Ex vivo autoradiography results of rat brain sections further confirmed the high uptake and retention of [99mTc]TRODAT-1 in the striatal region. In vitro binding studies measuring the affinity to dopamine transporters for the free ligand, TRODAT-1, and a nonradioactive rhenium derivative, Re-TRODAT-1, showed K i values of 9.7 nM and 14.1 nM, respectively. Behavioral studies in rats using the free ligand, TRODAT-1 and Re-TRODAT-1 indicated that, unlike other tropane derivatives, they displayed no effect on locomotor activity, suggesting low toxicity. These results strongly support the conclusions that this novel 99mTc radioligand binds selectively to dopamine transporters in the brain and that is is potentially useful for in vivo assessment of the loss of dopamine neurons in Parkinson’s and other neurodegenerative diseases.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    European journal of nuclear medicine 23 (1996), S. 1527-1530 
    ISSN: 1619-7089
    Keywords: Technetium-99m ; Single-photon emission tomography ; Basal ganglia ; Brain ; Parkinson's syndrome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Technetium-99m TRODAT-1, a tropane derivative, has shown promise as a tracer for the imaging of dopamine transporters in preliminary studies in rats and baboons. The present report concerns the first study of the use of [99mTc]TRODAT 1 for the same purpose in humans. The specific uptake of [99mTc]TRODAT1 in dopamine transporter sites located in the basal ganglia area was confirmed: the best contrast between the basal ganglia and the occipital area, which is devoid of dopamine transporters, was achieved at 120–140 min following injection. The development of a99mTc-based agent bypasses the need for cyclotron-produced radionuclides, which will be of benefit for routine clinical studies.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1619-7089
    Keywords: Striatum ; Single-photon emission tomography ; Dopamine neuron ; 6-OH-dopamine ; Autoradiography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Technetium-99m is the most commonly used radionuclide in routine nuclear medicine imaging procedures. Development of99mTc-labeled receptor-specific imaging agents for studying the central nervous system is potentially useful for evaluation of brain function in normal and disease states. A novel99mTc-labeled tropane derivative, [99mTc]TRODAT 1, which is useful as a potential CNS dopamine transporter imaging agent, was evaluated and characterized. After i.v. injection into rats, [99mTc]TRODAT-1 displayed specific brain uptake in the rat striatal region (striatum-cerebellum/cerebellum ratio 1.8 at 60 min), where dopamine neurons are concentrated. The specific striatal uptake could be blocked by pretreating rats with a dose of competing dopamine transporter ligand, ß-CIT (or RTI-55, i.v., 1 mg/kg). However, the specific striatal uptake of [99mTc]TRODAT-] was not affected by co-injection of excess free ligand (TRODAT-1, up to 200 μg per rat) or by pretreating the rats with haloperidol (i.v., 1 mg/kg). The specific uptake in striatal regions of rats that had prior 6-hydroxydopamine lesion in the substantia nigra area showed a dramatic reduction. The radioactive material recovered from the rat striatal homogenates at 60 min after i.v. injection of [99mTc]TRODAT-1 showed primarily the original compound (〉95%), a good indication of in vivo stability in brain tissue. Similar and comparable organ distribution patterns and brain regional uptakes of [99mTc]TRODAT-1 were obtained for male and female rats. Ex vivo autoradiography results of rat brain sections further confirmed the high uptake and retention of [99mTc]TRODAT-1 in the striatal region. In vitro binding studies measuring the affinity to dopamine transporters for the free ligand, TRODAT-1, and a nonradioactive rhenium derivative, Re-TRODAT-1, showed K i values of 9.7 nM and 14.1 nM, respectively. Behavioral studies in rats using the free ligand, TRODAT-1 and Re-TRODAT-1 indicated that, unlike other tropane derivatives, they displayed no effect on locomotor activity, suggesting low toxicity. These results strongly support the conclusions that this novel99mTc radioligand binds selectively to dopamine transporters in the brain and that is is potentially useful for in vivo assessment of the loss of dopamine neurons in Parkinson's and other neurodegeneralive diseases.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1619-7089
    Keywords: Key words: Brain ; Single-photon emission tomography ; Serotonin transporters ; [99mTc]TRODAT-1
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. [99mTc]TRODAT-1 was the first 99mTc-labeled imaging agent to show specific binding to dopamine transporters (DAT) in the striatum (STR) of human brain. Additionally, in vitro binding and autoradiographic experiments demonstrated that this tracer also binds to serotonin transporters (SERT) in the midbrain/hypothalamus (MB) area. In this study, [99mTc]TRODAT-1 was investigated as a potentially useful ligand to image SERT in the MB of living brain. A total of eight single-photon emission tomography (SPET) scans were performed in two baboons (Papio anubis) after intravenous (i.v.) injection of 740 MBq (20 mCi) of [99mTc]TRODAT-1 using a triple-head gamma camera equipped with ultra-high-resolution fan-beam collimators (scan time: 0–210 min). In four blocking studies, baboons were pretreated with (+)McN5652 (1 mg/kg, i.v.) or methylphenidate (1 mg/kg, i.v.) to specifically block SERT or DAT, respectively. After co-registration with magnetic resonance images of the same baboon, a region of interest analysis was performed using predefined templates to calculate specific uptake in the midbrain area and the striatum, with the cerebellum as the background region [(MB–CB)/CB, (STR–CB)/CB]. Additionally, two PET scans of the same baboons were performed after i.v. injections of 74–111 MBq (2–3 mCi) of [11C](+)McN5652 to identify the SERT sites. In [99mTc]TRODAT-1/SPET scans, the SERT sites in the MB region were clearly visualized. Semiquantitative analysis revealed a specific uptake in MB ([MB–CB]/CB) of 0.30±0.02, which was decreased to 0.040±0.005 after pretreatment with nonradioactive (+)McN5652, a selective SERT ligand. Pretreatment with methylphenidate reduced the specific binding of [99mTc]TRODAT-1 to DAT sites [(STR-CB)/CB] from 2.45±0.13 to 0.32±0.04 without any effect on its binding to SERT sites [(MB–CB)/CB], which was confirmed by the co-registration of the [11C](+)McN5652/PET scans. This preliminary study suggests that specific binding of [99mTc]TRODAT-1 to SERT sites can be detected by in vivo SPET imaging despite the low target to background ratio. These findings provide impetus for further development of similar compounds with improved binding affinity and selectivity to SERT sites.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1619-7089
    Keywords: Key words: Dopamine transporters ; Kinetic modeling ; Single-photon emission tomography ; Striatum ; Technetium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Accurate quantification of neuroreceptors requires full kinetic modeling of the dynamic single-photon emission tomography (SPET) or positron emission tomography (PET) images, with highly invasive arterial blood sampling. This study investigated the application of a reference region kinetic model to the dynamics of [99mTc]TRODAT-1 in nonhuman primates, obviating the need for blood sampling. A series of dynamic SPET scans were performed on two baboons following the injection of approximately 700 MBq of [99mTc]TRODAT-1. Rapid arterial blood samples were taken automatically during scanning. Reconstructed SPET images were co-registered with magnetic resonance imaging (MRI) scans of the baboons, and regions of interest (ROIs) placed on the striatum, cerebellum and cerebral hemispheres. The ROI data were combined with metabolite-corrected blood data, and fitted to a three-compartment kinetic model using nonlinear least squares techniques. The same data were also used in a simplified reference region model, in which the input function was derived from the nondisplaceable tissue compartment. In addition, semiquantitative blinded analysis was performed by three raters to determine the point of transient equilibrium in the specific binding curves. All methods generated values for the ratio of the kinetic rate constants k 3 /k 4, which gives an estimate of the binding potential, BP. These were compared with the full kinetic model. The mean values of k 3 /k 4 for the three different analysis techniques for each baboon were: 1.17±0.21 and 1.12±0.13 (full kinetic model), 0.93±0.13 and 0.90±0.07 (reference region model), and 0.97±0.18 and 0.92±0.08 (equilibrium method). The reference region method gave significantly lower results than the full kinetic model (P = 0.01), but it also produced a much smaller spread and better quality fits to the kinetic data. The reference region model results for k 3 /k 4 correlated very strongly with the full kinetic analysis (r 2 = 0.992, P〈0.001), and with the equilibrium model (r 2 = 0.88, P = 0.002). The subjectivity inherent in the equilibrium method produces inferior results compared with both kinetic analyses. It is suggested that the self-consistency of the reference region model, which requires no arterial blood sampling, provides a more precise and reliable estimate of the binding of [99mTc]TRODAT-1 to dopamine transporters than full kinetic modeling. The reference region method is also better suited to a routine clinical environment, and would be able to distinguish smaller differences in dopaminergic function between patient groups.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1619-7089
    Keywords: Key words: Serotonin transporter ; Selective serotonin reuptake inhibitor ; 5-Hydroxytryptamine ; Baboon ; Single-photon emission tomography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. A new radioligand, 5-iodo-2-[[2–2-[(dimethylamino)methyl]phenyl]thio]benzyl alcohol ([123I]IDAM), has been developed for selective single-photon emission tomography (SPET) imaging of SERT. In vitro binding studies suggest a high selectivity of IDAM for SERT (K i=0.097 nM), with considerably lower affinities for norepinephrine and dopamine transporters (NET K i= 234 nM and DAT K i〉10 µM, respectively). In this study the biodistribution of SERT in the baboon brain was investigated in vivo using [123I]IDAM and SPET imaging. Dynamic sequences of SPET scans were performed on three female baboons (Papio anubis) after injection of 555 MBq of [123I]IDAM. Displacing doses (1 mg/kg) of the selective SERT ligand (+)McN5652 were administered 90–120 min after injection of [123I]IDAM. Similar studies were performed using a NET inhibitor, nisoxetine, and a DAT blocker, methylphenidate. After 60–120 min, the regional distribution of tracer within the brain reflected the characteristic distribution of SERT, with the highest uptake in the midbrain area (hypothalamus, raphe nucleus, substantia nigra), and the lowest uptake in the cerebellum (an area presumed free of SERT). Peak specific binding in the midbrain occurred at 120 min, with a ratio to the cerebellum of 1.80±0.13. At 30 min, 85% of the radioactivity in the blood was metabolite. Following injection of a competing SERT ligand, (+)McN5652, the tracer exhibited rapid washout from areas with high concentrations of SERT (dissociation rate constant in the midbrain, averaged over three baboons, k off=0.025±0.002 min–1), while the cerebellar activity distribution was undisturbed (washout rate 0.0059± 0.0003 min–1). Calculation of tracer washout rate pixel-by-pixel enabled the generation of parametric images of the dissociation rate constant. Similar studies using nisoxetine and methylphenidate had no effect on the distribution of [123I]IDAM in the brain. These results suggest that [123I]IDAM is suitable for selective SPET imaging of SERT in the primate brain, with high contrast, favorable kinetics, and negligible binding to either NET or DAT.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1619-7089
    Keywords: Dopamine transporters Kinetic modeling Single-photon emission tomography Striatum Graphical analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Quantification of dopamine transporters (DAT) using [99mTc]TRODAT-1 and single-photon emission tomography (SPET) requires full kinetic modeling of the data, using complex and invasive arterial blood sampling to provide an input function to the model. We have shown previously that a simpler reference tissue model provides accurate quantitative results, using a reference region devoid of DAT as the input to the model and thereby obviating the need for blood sampling. We now extend this work into humans, and develop further simplifications to make the imaging protocol much more practical as a routine procedure. Fourteen healthy subjects (age 29.8±8.4 years, range 18.7–45.5 years) underwent dynamic SPET for 6 h following injection of 752±28 MBq [99mTc]TRODAT-1. The kinetic data were analyzed using nonlinear regression analysis (NLRA) and Logan-Patlak graphical analysis. In addition, simple average ratios of striatal-to-background counts were obtained for three 1-h periods (3–4 h, 4–5 h, 5–6 h), and compared against the kinetic models. All methods gave an index of specific binding, proportional to the binding potential, known as the distribution volume ratio (DVR). The reference tissue NLRA gave mean values of k 3=0.013±0.003 min–1, k 4=0.011±0.002 min–1, and DVR=2.29±0.17. Graphical analysis gave a value of DVR=2.28±0.16, and the three ratio values of DVR were: 3–4 h, 2.18±0.15; 4–5 h, 2.34±0.13; and 5–6 h, 2.46±0.19. Graphical analysis was highly correlated with NLRA (R 2=0.91, slope=0.90±0.08). The ratio methods correlated well with NLRA (3–4 h, R 2=0.71, slope=0.73±0.13; 4–5 h, R 2=0.86, slope=0.73±0.09; 5–6 h, R 2=0.80, slope=1.00±0.15), and also with graphical analysis (3–4 h, R 2=0.65, slope=0.74±0.16; 4–5 h, R 2=0.85, slope=0.78±0.09; 5–6 h, R 2=0.88, slope=1.11±0.12). The optimum equilibrium time point for obtaining a simple ratio was approximately 4.5–5.5 h. In conclusion, the simple ratio techniques for obtaining a quantitative measure of specific binding correlated well with the reference tissue kinetic models, using both NLRA and graphical analysis. The optimum time for obtaining a ratio appeared to be in the range 4.5–5.5 h. Earlier time points, while still relatively accurate, had a lower sensitivity and may not be optimized for measuring small changes in DAT concentrations.
    Type of Medium: Electronic Resource
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