Radiosynthesis and in vitro evaluation of 2-(N-alkyl-N-1'-11C-propyl)amino-5-hydroxytetralin analogs as high affinity agonists for dopamine D-2 receptors

Nucl Med Biol. 1999 Oct;26(7):725-35. doi: 10.1016/s0969-8051(99)00051-7.

Abstract

We have developed radiotracers based on agonists that may potentially allow the in vivo assessment of the high affinity (HA) state of the dopamine D-2 receptors. The population of HA state, which is likely the functional state of the receptor, may be altered in certain diseases. We carried out radiosyntheses and evaluated the binding affinities, lipophilicity, and in vitro autoradiographic binding characteristics of three dopamine D-2 receptor agonists: (+/-)-2-(N,N-dipropyl)amino-5-hydroxytetralin (5-OH-DPAT), (+/-)-2-(N-phenethyl-N-propyl)amino-5-hydroxytetralin (PPHT), and (+/-)-2-(N-cyclohexylethyl-N-propyl)amino-5-hydroxytetralin (ZYY-339). In 3H-spiperone assays using rat striata, ZYY-339 exhibited subnanomolar affinity for D-2 receptor sites (IC50 = 0.010 nM), PPHT was somewhat weaker (IC50 = 0.65 nM), and 5-OH-DPAT exhibited the weakest affinity (IC50 = 2.5 nM) of the three compounds. Radiosynthesis of these derivatives, 2-(N-propyl-N-1'-11C-propyl)amino-5-hydroxytetralin (11C-5-OH-DPAT), 2-(N-phenethyl-N-1'-11C-propyl)amino-5-hydroxytetralin (11C-PPHT), and 2-(N-cyclohexylethyl-N-1'-11C-propyl)amino-5-hydroxytetralin (11C-ZYY-339) was achieved by first synthesizing 11C-1-propionyl chloride and subsequent coupling with the appropriate secondary amine precursor to form the respective amide, which was then reduced to provide the desired tertiary amine products. The final products were obtained by reverse-phase high performance liquid chromatography (HPLC) purification in radiochemical yields of 5-10% after 60-75 min from the end of 11CO2 trapping and with specific activities in the range of 250-1,000 Ci/mmol. In vitro autoradiographs in rat brain slices with 11C-5-OH-DPAT, 11C-PPHT, and 11C-ZYY-339 revealed selective binding of the three radiotracers to the dopamine D-2 receptors in the striata.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / analogs & derivatives
  • 8-Hydroxy-2-(di-n-propylamino)tetralin / chemical synthesis
  • 8-Hydroxy-2-(di-n-propylamino)tetralin / chemistry
  • 8-Hydroxy-2-(di-n-propylamino)tetralin / metabolism
  • Animals
  • Autoradiography
  • Brain / metabolism
  • Carbon Radioisotopes / chemistry
  • Dopamine Agonists / chemical synthesis*
  • Dopamine Agonists / chemistry
  • Dopamine Agonists / metabolism*
  • Dopamine Antagonists / metabolism
  • Isotope Labeling
  • Male
  • Phenethylamines / chemical synthesis
  • Phenethylamines / chemistry
  • Phenethylamines / metabolism
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / metabolism*
  • Tetrahydronaphthalenes / chemical synthesis
  • Tetrahydronaphthalenes / chemistry
  • Tetrahydronaphthalenes / metabolism

Substances

  • Carbon Radioisotopes
  • Dopamine Agonists
  • Dopamine Antagonists
  • Phenethylamines
  • Radiopharmaceuticals
  • Receptors, Dopamine D2
  • Tetrahydronaphthalenes
  • ZYY 339
  • 5-hydroxy-2-N,N-dipropylaminotetralin
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • 2-(N-phenethyl-N-propyl)amino-5-hydroxytetralin