Disease relevance of RTI 55

• BACKGROUND: Dopaminergic loss can be visualized by means of iodine I 123-labeled 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([(123)I]beta-CIT) single-photon emission computed tomography (SPECT) in several neurodegenerative parkinsonian disorders [1].
• DAT mRNA in SNC was also significantly increased 96 hr after ischemia, which corresponded with the increase of [125I] beta-CIT binding [2].
• OBJECTIVE: To assess the accuracy and clinical usefulness of [(123)I]beta-CIT (2beta-carbomethoxy-3beta-(4-iodophenyl)tropane) SPECT in the differential diagnosis of Parkinson's disease [3].
• RESULTS: beta-CIT uptake was significantly lower in the whole striatum as well as separately in the putamen and in the caudate nucleus in Parkinson's disease than in the reference group or in drug induced movement disorder, essential tremor, or dystonia [3].
• Measurement of the dopaminergic degeneration in Parkinson's disease with [123I] beta-CIT and SPECT. Correlation with clinical findings and comparison with multiple system atrophy and progressive supranuclear palsy [4].

Psychiatry related information on RTI 55

• Behavioral experiments in mice showed that both beta-CDIT and beta-CIT induced stimulation of locomotor activity [5].

High impact information on RTI 55

• Both cocaine and RTI-55 inhibited 5HT uptake by dSERT with estimated inhibition constants of approximately 500 nM, while high concentrations (> 10 microM) of dopamine, norepinephrine, octopamine, tyramine, and histamine failed to inhibit transport [6].
• Specific binding of RTI-233 to the rat serotonin transporter, purified from Sf-9 insect cells, was demonstrated by the competitive inhibition of fluorescence using excess serotonin, citalopram, or RTI-55 (2beta-carbomethoxy-3beta-(4-iodophenyl)tropane) [7].
• Elevated striatal dopamine transporters during acute cocaine abstinence as measured by [123I] beta-CIT SPECT [8].
• Animals with greater beta-CIT binding and low CSF 5-HIAA concentrations displayed greater aggressiveness and were less sensitive to alcohol-induced intoxication [9].
• RESULTS: We found significant differences in displaceable [123I] beta-CIT binding in the region corresponding to thalamus/hypothalamus between the summer group and the winter group (1.9 +/- 0.3 vs. 1.4 +/- 0.2, respectively; p < .01) [10].

Chemical compound and disease context of RTI 55

• We studied a correlation of urinary dysfunction with nigrostriatal dopaminergic deficit in Parkinson's disease (PD) by single-photon emission computed tomography (SPECT) imaging of dopamine transporter with [123I]-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane (beta-CIT) [11].
• Previous exposure to cocaine significantly affected locomotor activity and stereotopy-like behavior produced by cocaine, mazindol, RTI-55, and GBR12909 [12].
• In depression as well as in bulimia, selective serotonin reuptake inhibitors significantly decreased the beta-CIT binding potential, however, no significant dose relationship has been obtained in depression [13].

Biological context of RTI 55

• These studies demonstrate beta-CIT stereoselectivity using both homogenate binding and in vivo imaging and suggest that the inactive enantiomer may be a useful measure of the kinetics of both blood-brain barrier transport and nonspecific binding [14].
• METHODS: We assessed genotype at the SLC6A3 promoter VNTR polymorphism in 96 healthy European Americans (age range, 18-88 y) who also underwent SPECT with (123)I-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane (beta-CIT) for measurement of striatal DAT protein availability [15].
• However, since [123I] beta-CIT binding is normal, a decreased number of D2-receptors or a decreased affinity of D2-receptors for [123I]IBZM is more likely than an increased level of synaptic DA with attendant downregulation of D2-receptors [16].
• Saturation binding site analysis demonstrated an increase in the density of RTI-55 binding sites with no change in the affinity of the radioligand for the SERT [17].
• We conclude that with no mutagenic effects and LD50 more than 6 orders of magnitude higher than the routinely used doses in PET or SPET, it can be assumed that beta-CIT can be safely used as a radioligand in humans [18].

Anatomical context of RTI 55

• The relative reduction in [123I] beta-CIT uptake in the hemi-PD patients was greater in the putamen than in the caudate [19].
• RESULTS: A significant negative correlation was found between a measure of overall tic severity and beta-CIT binding in the midbrain (r = -0.73, p = 0.02) and the thalamus (r = -0.82, p < 0.01) [20].
• Cocaine and its analog RTI-55 [2 beta-carbomethoxy-3 beta-(4-iodophenyl-) tropane] inhibited the binding of haloperidol to placental membranes with appreciable potency [21].
• This increase of [125I] beta-CIT binding does not come from de novo expression of DAT in glial cells in the damaged area in CPu [2].
• Peak uptake of [123I] beta-CIT-FP into the basal ganglia occurred earlier (3-4 h after injection of tracer) than that of [123I] beta-CIT (> 8 h) [22].

Associations of RTI 55 with other chemical compounds

• These data demonstrate that SPECT imaging of the dopamine transporter with [123I] beta-CIT can identify patients with PD at the onset of motor symptoms and suggest that this technique also may be useful in identifying individuals with developing dopaminergic pathology before onset of motor symptoms [19].
• This report concerns the synthesis and chemical characterization of novel series of N-substituted 2 beta-carbomethoxy-3 beta-(4'-iodophenyl)tropane (beta-CIT, 2) analogs and their neuropharmacological evaluation for affinity at dopamine (DAT), serotonin (5-HTT), and norepinephrine membrane transporters in rat brain tissue [23].
• 2beta-Carbomethoxy-3beta-(4-iodophenyl)nortropane (nor-beta-CIT) is a des-methyl analogue of beta-CIT, which in vitro has tenfold higher affinity (IC50=0.36 nM) to the serotonin transporter than beta-CIT (IC50=4.2 nM) [24].
• To visualize possible alterations of the pre- and postsynaptic side of striatal dopaminergic synapses, SPECT studies using the radiotracers [123I] epidepride and [123I] beta-CIT were performed in 10 patients with idiopathic cervical dystonia [25].
• Serotonin transporter density in cell membranes was monitored by measuring paroxetine-sensitive binding of RTI-55, a specific high-affinity ligand for the transporter [26].

Gene context of RTI 55

• Several active analogues were also evaluated for their ability to block uptake of DA, 5-HT, and NE and inhibit binding of [(125)I] RTI-55 at HEK-hDAT, HEK-hSERT, and HEK-hNET cells [27].
• Synthesis and monoamine transporter affinity of 3'-analogs of 2-beta-carbomethoxy-3-beta-(4'-iodophenyl)tropane (beta-CIT) [28].
• RTI-55 had similar affinity for the hDAT and hSERT and lower affinity for hNET (Kd = 1 [29].
• Thus, we applied the high-resolution SPECT to in vivo imaging of the brain dopaminergic neurotransmission system in common marmosets using two radiolabeled ligands, [123I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane (beta-CIT) as a dopamine transporter (DAT) ligand and [123I]iodobenzamide (IBZM) as a dopamine D2 receptor (D2R) ligand [30].
• RESULTS: The beta-CIT binding for the DAT was increased significantly in the caudate-putamen (CPu) of SH rats compared with that of Wistar-Kyoto (WKY) rats at both pre- and posthypertensive stages [31].

Analytical, diagnostic and therapeutic context of RTI 55

• More recent studies have used surrogate markers of the integrity of nigrostriatal function such as striatal uptake of fluorodopa on positron emission tomography (PET) or beta-CIT-on single-photon emission computerized tomography (SPECT) as primary outcome measures [32].
• At present, preparation of no-carrier-added (NCA) [123I] beta-CIT is achieved by iododestannylation of a trialkylstannyl precursor with sodium [123I]iodide in the presence of oxidizing agent, followed by preparative HPLC [33].
• METHODS: The amounts of the dopamine transporter (DAT) and dopamine D1 and D2 receptors in the brain were assessed by in vitro autoradiography with the ligands [125I] beta-CIT, [125I]SCH23982 and [125I]iodospiperone, respectively [31].
• A comparison of the ultrafiltration system with equilibrium dialysis revealed < 5% difference for beta-CIT and iomazenil, but 16% for IBF [34].
• These data demonstrate that the dopaminergic nerve cell loss in PD and other disorders with a dopaminergic lesion can be quantified with [123I] beta-CIT and SPECT and that hopefully a preclinical or very early diagnosis is made possible [4].

References