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  • 1
    Electronic Resource
    Electronic Resource
    Synthesis and structure of two organozirconocenes with .alpha. nitrogen substituents (1992)
    s.l. : American Chemical Society
    Organometallics 11 (1992), S. 122-127 
    Details
    ISSN: 1520-6041
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/om00037a027
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  • 2
    Electronic Resource
    Electronic Resource
    First Example of a 99mTc Complex as a Dopamine Transporter Imaging Agent (1995)
    s.l. : American Chemical Society
    Journal of the American Chemical Society 117 (1995), S. 11037-11038 
    Details
    ISSN: 1520-5126
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/ja00149a039
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  • 3
    Electronic Resource
    Electronic Resource
    Imaging of dopamine transporters in humans with technetium-99m TRODAT 1 (1996)
    Springer
    European journal of nuclear medicine 23 (1996), S. 1527-1530 
    Details
    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
    URL: http://dx.doi.org/10.1007/BF01254479
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  • 4
    Electronic Resource
    Electronic Resource
    In vivo imaging of serotonin transporters with [99mTc]TRODAT-1 in nonhuman primates (1999)
    Springer
    European journal of nuclear medicine 26 (1999), S. 342-347 
    Details
    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
    URL: http://dx.doi.org/10.1007/s002590050396
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  • 5
    Electronic Resource
    Electronic Resource
    [99mTc]TRODAT-1: a novel technetium-99m complex as a dopamine transporter imaging agent (1997)
    Springer
    European journal of nuclear medicine 24 (1997), S. 372-380 
    Details
    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
    URL: http://dx.doi.org/10.1007/BF00881808
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  • 6
    Electronic Resource
    Electronic Resource
    Pharmacological effects of dopaminergic drugs on in vivo binding of [99mTc]TRODAT-1 to the central dopamine transporters in rats (1997)
    Springer
    European journal of nuclear medicine 25 (1997), S. 31-39 
    Details
    ISSN: 1619-7089
    Keywords: Key words: Brain ; Parkinson’s disease ; Dopamine transporter ligands ; Single-photon emission tomography ; In vivo binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: R -(exo-exo)]-, [99mTc]TRODAT-1, to DAT. This paper describes the further characterization of [99mTc]TRODAT-1 binding sites in rats under conditions which may exist in patients receiving various drug treatments. All experiments were carried out using an i.v. injection of [99mTc]TRODAT-1 into male Sprague-Dawley rats. Measurements of % dose/gram ratio of (striatum–cerebellum)/cerebellum at 1 h post injection were used as an indicator for specific DAT binding. The biodistribution studies were performed in the presence of drugs which compete for the binding site, such as CFT (WIN 35,428) and methylphenidate, drugs which influence dopamine levels, such as l-DOPA, γ-hydroxybutyrolactone, and α-methyl-p-tyrosine, and d-amphetamine, which both acts as a competitor for DAT binding and increases dopamine levels. Additionally, the influence of dopamine receptor agonists, such as apomorphine and (+)bromocriptine, on biodistribution was tested. Binding of [99mTc]TRODAT-1 to DAT was found to be inhibited by CFT, methylphenidate, and d-amphetamine in a dose-dependent manner. The specific binding of [99mTc]TRODAT-1 was not altered by dopamine receptor agonists or by drugs which cause minor changes in dopamine levels. When administered in high doses (634 μmol/kg), l-DOPA also decreased the binding of [99mTc]TRODAT-1. It is likely that a low dose of l-DOPA (normally needed in the treatment of Parkinson’s disease) will not affect the results on [99mTc]TRODAT-1 single-photon emission tomographic (SPET) imaging studies. In conclusion, the results clearly demonstrate the specificity of [99mTc]TRODAT-1 binding to DAT in vivo. Competition for [99mTc]TRODAT-1 binding was observed only with drug treatment that significantly increases dopamine levels or actively competes for binding at DAT. The results suggest that prior knowledge of whether patients are receiving various drug treatments may assist in the interpretation of DAT status as assessed by SPET imaging studies using [99mTc]TRODAT-1.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002590050191
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  • 7
    Electronic Resource
    Electronic Resource
    Single-photon emission tomography imaging of serotonin transporters in the nonhuman primate brain with [123I]ODAM (1999)
    Springer
    European journal of nuclear medicine 26 (1999), S. 1359-1362 
    Details
    ISSN: 1619-7089
    Keywords: Key words. Serotonin transporter ; SSRI ; 5-Hydroxytryptamine ; Single-photon emission tomography ; Baboon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. We have described previously a selective serotonin transporter (SERT) radioligand, [123I]IDAM. We now report a similarly potent, but more stable IDAM derivative, 5-iodo-2-[2-[(dimethylamino)methyl]phenoxy]benzyl alcohol ([123I]ODAM). The imaging characteristics of this radioligand were studied and compared against [123I]IDAM. Dynamic sequences of single-photon emission tomography (SPET) scans were obtained on three female baboons after injection of 375 MBq of [123I]ODAM. Displacing doses (1 mg/kg) of the selective SERT ligand (+)McN5652 were administered 120 min after injection of [123I]ODAM. Total integrated brain uptake of [123I]ODAM was about 30% higher than [123I]IDAM. After 60–120 min, the regional distribution of tracer within the brain reflected the characteristic distribution of SERT. Peak specific binding in the midbrain occurred 120 min after injection, with an equilibrium midbrain to cerebellar ratio of 1.50±0.08, which was slightly lower than the value for [123I]IDAM (1.80± 0.13). Both the binding kinetics and the metabolism of [123I]ODAM were slower than those of [123I]IDAM. Following injection of a competing SERT ligand, (+)McN5652, the tracer exhibited washout from areas with high concentrations of SERT, with a dissociation kinetic rate constant k off=0.0085±0.0028 min–1 in the midbrain. Similar studies using nisoxetine and methylphenidate showed no displacement, consistent with its low binding affinity to norepinephrine and dopamine transporters, respectively. These results suggest that [123I]ODAM is suitable for selective SPET imaging of SERT in the primate brain, with higher uptake and slower kinetics and metabolism than [123I]IDAM, but also a slightly lower selectivity for SERT.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002590050596
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  • 8
    Electronic Resource
    Electronic Resource
    Development of 99mTc-labelled complexes for imaging dopamine transporters in the brain (1998)
    Springer
    Transition metal chemistry 23 (1998), S. 531-536 
    Details
    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
    URL: http://dx.doi.org/10.1023/A:1006921811871
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  • 9
    Electronic Resource
    Electronic Resource
    Simplified reference region model for the kinetic analysis of [99mTc]TRODAT-1 binding to dopamine transporters in nonhuman primates using single-photon emission tomography (1999)
    Springer
    European journal of nuclear medicine 26 (1999), S. 518-526 
    Details
    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
    URL: http://dx.doi.org/10.1007/s002590050420
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  • 10
    Electronic Resource
    Electronic Resource
    [99mTc]TRODAT-1: A novel technetium-99m complex as a dopamine transporter imaging agent (1997)
    Springer
    European journal of nuclear medicine 24 (1997), S. 372-380 
    Details
    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
    URL: http://dx.doi.org/10.1007/BF00881808
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