title: Effect of cyclosporin A on the uptake of D3-selective PET radiotracers in rat brain.
abstract: BACKGROUND
  Four benzamide analogs having a high affinity and selectivity for D(3) versus D(2) receptors were radiolabeled with (11)C or (18)F for in vivo evaluation.
  
  
  METHODS
  Precursors were synthesized, and the four D(3) selective benzamide analogs were radiolabeled. The tissue distribution and brain uptake of the four compounds were evaluated in control rats and rats pretreated with cyclosporin A, a modulator of P-glycoprotein and an inhibitor of other ABC efflux transporters that contribute to the blood brain barrier. Micro-positron emission tomographic (PET) imaging was carried out for [(11)C]6 in a control and a cyclosporin A pretreated rat.
  
  
  RESULTS
  All four compounds showed low brain uptake in control rats at 5 and 30 min post-injection; despite recently reported rat behavioral studies conducted on analogs 6 (WC-10) and 7 (WC-44). Following administration of cyclosporin A, increased brain uptake was observed with all four PET radiotracers at both 5 and 30 min post-intravenous injection. An increase in brain uptake following modulation/inhibition of the ABC transporters was also observed in the microPET study.
  
  
  CONCLUSIONS
  These data suggest that D3 selective conformationally-flexible benzamide analogs which contain a N-2-methoxyphenylpiperazine moiety are substrates for P-glycoprotein or other adenosine triphosphate (ATP)-binding cassette transporters expressed at the blood-brain barrier, and that PET radiotracers containing this pharmacophore may display low brain uptake in rodents due to the action of these efflux transporters.
authors: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Zhude
authors: Z
authors: Tu
authors: Shihong
authors: S
authors: Li
authors: Jinbin
authors: J
authors: Xu
authors: Wenhua
authors: W
authors: Chu
authors: Lynne A
authors: LA
authors: Jones
authors: Robert R
authors: RR
authors: Luedtke
authors: Robert H
authors: RH
authors: Mach
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D002250:Carbon Radioisotopes; D016572:Cyclosporine / Q000494:pharmacology*; D005462:Fluorine Radioisotopes; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D001549:Benzamides; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D050637:Receptors, Dopamine D3; D016572:Cyclosporine; D000262:Adenylyl Cyclases