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Ligands of glutamate and dopamine receptors evenly labeled with hydrogen isotopes

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A reaction of high-temperature solid-phase catalytic isotope exchange (HSCIE) was studied for the preparation of tritium- and deuterium-labeled ligands of glutamate and dopamine receptors. Tritium-labeled (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclopenten-5,1-imine ([G-3H]MK-801) and R(+)-7-hydroxy-N,N-di-n-propyl-2-aminotetraline ([G-3H]-7-OH-DPAT) were obtained with a specific activity of 210 and 120 Ci/mol, respectively. The isotopomeric distribution of deuterium-labeled ligands was studied using time-of-flight mass-spectrometer MX 5310 (ESI-o-TOF) with electrospray and orthogonal ion injection. Mean deuterium incorporation per ligand molecule was 11.09 and 3.21 atoms for [G-3H]MK-801 and [G-3H]-7-OH-DPAT, respectively. The isotope label was shown to be distributed all over the ligand molecule. The radioreceptor binding of tritium-labeled ligands [G-3H]MK-801 and [G-3H]-7-OH-DPAT was analyzed using the brain structure of Vistar rats. It was demonstrated that [G-3H]MK-801 specifically binds to hippocampus membranes with K d 8.3 ± 1.4 nM, B max being 3345 ± 300 fmol/mg protein. The [G-3H]-7-OH-DPAT ligand specifically binds to rat striatum membranes with K d 10.01 ± 0.91 nM and B max 125 ± 4.5 fmol/mg protein. It was concluded that the HSCIE reaction can be used for the preparation of highly tritium-labeled (+)-MK-801 and 7-OH-DPAT with retention of their physiological activities.

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Abbreviations

HS:

hydrogen spillover

HSCIE:

high-temperature solid-phase catalytic isotope exchange

7-OH-DPAT:

R(+)-7-hydroxy-N,N-di-n-propyl-2-aminotetraline

MK-801:

(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclopenten-5,1-imine

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Correspondence to Yu. A. Zolotarev.

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Original Russian Text © Yu.A. Zolotarev, Yu.Yu. Firsova, A. Abaimov, A.K. Dadayan, V.S. Kosik, A. V. Novikov, N.V. Krasnov, B. V. Vaskovskii, I.V. Nazimov, G.I. Kovalev, N.F. Myasoedov, 2009, published in Bioorganicheskaya Khimiya, 2009, Vol. 35, No. 3, pp. 323–333.

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Zolotarev, Y.A., Firsova, Y.Y., Abaimov, A. et al. Ligands of glutamate and dopamine receptors evenly labeled with hydrogen isotopes. Russ J Bioorg Chem 35, 296–305 (2009). https://doi.org/10.1134/S1068162009030030

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  • DOI: https://doi.org/10.1134/S1068162009030030

Key words

  • dopamine receptors
  • glutamate receptors
  • receptor ligands
  • tritium- and deuterium labeled
  • spillover hydrogen