RTI-55

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RTI-55
Beta-CIT.png
Systematic (IUPAC) name
Methyl (1R,2S,3S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
Clinical data
Legal status
  • UK: Class A
Identifiers
CAS number 133647-95-7 YesY
ATC code ?
PubChem CID 108220
Synonyms (–)-2β-Carbomethoxy-3β-(4-iodophenyl)tropane; β-CIT
Chemical data
Formula C16H20INO2 
Mol. mass 385.24 g/mol
 YesY (what is this?)  (verify)

RTI-55 (iometopane) is a phenyltropane-based psychostimulant used in scientific research and with some medical application/s. This drug was first cited in 1991.[1] RTI-55 is a non-selective dopamine reuptake inhibitor derived from methylecgonidine. However, more selective analogs are derived by conversion to "pyrrolidinoamido" RTI-229, for instance. Due to the large bulbous nature of the weakly electron withdrawing iodo halogen atom, RTI-55 is the most strongly serotonergic of the simple para-substituted troparil based analogs.[2] In rodents RTI-55 actually caused death at a dosage of 100 mg/kg, whereas RTI-51 and RTI-31 did not.[2] Another notable observation is the strong propensity of RTI-55 to cause locomotor activity enhancements,[2] although in an earlier study, RTI-51 was actually even stronger than RTI-55 in shifting baseline LMA.[3] This observation serves to highlight the disparities that can arise between studies.

RTI-55 is one of the most potent phenyltropane stimulants commercially available, which limits its use in humans, as it might have significant abuse potential if used outside of a strictly controlled medical setting.[4] However, it is definitely worthy of mentioning that increasing the size of the halogen atom attached to troparil serves to reduce the number of lever responses in a session when these analogs were compared in a study.[5] Although RTI-55 wasn't specifically examined in this study the number of lever responses in a given session was of the order cocaine > WIN35428 > RTI-31 > RTI-51.

In contrast to RTI-31 which is predominantly dopaminergic, increasing the size of the covalently bonded halogen from a chlorine to an iodine markedly increases the affinity for the SERT, while retaining mostly all of its DAT blocking activity.

If desired, a radioactive source of iodine can be utilized.

I123 and I125 in particular because these are very high energy γ-ray emitters.

Compared to the "WIN" compounds, extremely low Ki values are attainable.

Uses[edit]

RTI-55 is mainly used in scientific research into the dopamine reuptake transporter. Various radiolabelled forms of RTI-55 (with different radioactive isotopes of iodine used depending on the application) are used in both humans and animals to map the distribution of dopamine transporters and serotonin transporters in the brain.[6][7] The 123I derivative is known as iometopane.

The main practical application for this drug in medicine is to assess the rate of dopamine neuron degradation in the brains of sufferers of PD,[8][9] and some other conditions such as progressive supranuclear palsy.[10]

Chemistry[edit]

RTI-55 is made as follows:[11][12][13]

RTI-55 Syntheses.png

See also[edit]

References[edit]

  1. ^ Boja, J. W.; Patel, A.; Carroll, F. I.; Rahman, M. A.; Philip, A.; Lewin, A. H.; Kopajtic, T. A.; Kuhar, M. J. (1991). "125IRTI-55: a potent ligand for dopamine transporters". European Journal of Pharmacology 194 (1): 133–134. doi:10.1016/0014-2999(91)90137-F. PMID 2060590.  edit
  2. ^ a b c Carroll, F. I.; Runyon, S. P.; Abraham, P.; Navarro, H.; Kuhar, M. J.; Pollard, G. T.; Howard, J. L. (2004). "Monoamine Transporter Binding, Locomotor Activity, and Drug Discrimination Properties of 3-(4-Substituted-phenyl)tropane-2-carboxylic Acid Methyl Ester Isomers". Journal of Medicinal Chemistry 47 (25): 6401–6409. doi:10.1021/jm0401311. PMID 15566309.  edit
  3. ^ Kimmel, HL; Carroll; Kuhar (2001). "Locomotor stimulant effects of novel phenyltropanes in the mouse". Drug and alcohol dependence 65 (1): 25–36. doi:10.1016/S0376-8716(01)00144-2. PMID 11714587.  edit
  4. ^ Weed, M. R.; MacKevicius, A. S.; Kebabian, J.; Woolverton, W. L. (1995). "Reinforcing and discriminative stimulus effects of beta-CIT in rhesus monkeys". Pharmacology, biochemistry, and behavior 51 (4): 953–956. doi:10.1016/0091-3057(95)00032-r. PMID 7675883.  edit
  5. ^ Wee, S.; Carroll, F.; Woolverton, W. (2006). "A reduced rate of in vivo dopamine transporter binding is associated with lower relative reinforcing efficacy of stimulants". Neuropsychopharmacology 31 (2): 351–362. doi:10.1038/sj.npp.1300795. PMID 15957006.  edit
  6. ^ Shaya, E.; Scheffel, U.; Dannals, R.; Ricaurte, G.; Carroll, F.; Wagner Jr, J.; Kuhar, M.; Wong, D. (1992). "In vivo imaging of dopamine reuptake sites in the primate brain using single photon emission computed tomography (SPECT) and iodine-123 labeled RTI-55". Synapse 10 (2): 169–172. doi:10.1002/syn.890100210. PMID 1585258.  edit
  7. ^ Shang, Y.; Gibbs, M.; Marek, G.; Stiger, T.; Burstein, A.; Marek, K.; Seibyl, J.; Rogers, J. (2007). "Displacement of serotonin and dopamine transporters by venlafaxine extended release capsule at steady state: a 123I2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane single photon emission computed tomography imaging study". Journal of Clinical Psychopharmacology 27 (1): 71–75. doi:10.1097/JCP.0b013e31802e0017. PMID 17224717.  edit
  8. ^ Staffen, W.; Mair, A.; Unterrainer, J.; Trinka, E.; Bsteh, C.; Ladurner, G. (2000). "123I beta-CIT binding and SPET compared with clinical diagnosis in parkinsonism". Nuclear medicine communications 21 (5): 417–424. doi:10.1097/00006231-200005000-00002. PMID 10874697.  edit
  9. ^ Zubal, I.; Early, M.; Yuan, O.; Jennings, D.; Marek, K.; Seibyl, J. (2007). "Optimized, automated striatal uptake analysis applied to SPECT brain scans of Parkinson's disease patients". Journal of Nuclear Medicine 48 (6): 857–864. doi:10.2967/jnumed.106.037432. PMID 17504864.  edit
  10. ^ Seppi, K.; Scherfler, C.; Donnemiller, E.; Virgolini, I.; Schocke, M. F. H.; Goebel, G.; Mair, K. J.; Boesch, S.; Brenneis, C.; Wenning, G. K.; Poewe, W. (2006). "Topography of dopamine transporter availability in progressive supranuclear palsy: a voxelwise 123Ibeta-CIT SPECT analysis". Archives of Neurology 63 (8): 1154–1160. doi:10.1001/archneur.63.8.1154. PMID 16908744.  edit
  11. ^ U.S. Patent 5,128,118
  12. ^ U.S. Patent 6,123,917
  13. ^ Musachio, J.; Keverline, K.; Carroll, F.; Dannals, R. (1996). "3 Beta-(p-trimethylsilylphenyl)tropane-2 beta-carboxylic acid methyl ester: a new precursor for the preparation of 123IRTI-55". Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine 47 (1): 79–81. PMID 8589674.  edit