Radiolabelling and PET brain imaging of the ¦Á₁-adrenoceptor antagonist Lu AE43936

详细信息    查看全文

• 作者：Rune Risgaard^a ; ¹ ; Anders Ettrup^b ; ¹ ; Thomas Balle^a ; ^c ; Agnete Dyssegaard^b ; Hanne Demant Hansen^b ; Szabolcs Lehel^d ; Jacob Madsen^d ; Henrik Pedersen^e ; Ask Pü ; schl^e ; Lassina Badolo^e ; Benny Bang-Andersen^e ; Gitte Moos Knudsen^b ; Jesper Langgaard Kristensen^a ; ^{jesper.kristensen@sund.ku.dk}
• 关键词：PET ; ¦Á1-adrenoceptor ; Antagonist ; Octoclothepin ; Radiolabelling ; Permeability
• 刊名：Nuclear Medicine and Biology
• 出版年：2013
• 出版时间：January, 2013
• 年：2013
• 卷：40
• 期：1
• 页码：135-140
• 全文大小：770 K

文摘

Cerebral ¦Á₁-adrenoceptors are a common target for many antipsychotic drugs. Thus, access to positron emission tomography (PET) brain imaging of ¦Á₁-adrenoceptors could make important contributions to the understanding of psychotic disorders as well as to the pharmacokinetics and occupancy of drugs targeting the ¦Á₁-adrenoceptors. However, so far no suitable PET radioligand has been developed for brain imaging of ¦Á₁-adrenoceptors. Here, we report the synthesis of both enantiomers of the desmethyl precursors of the high affinity ¦Á₁-adrenoceptor ligand (). The two enantiomers of were subsequently [¹¹C] radiolabelled and evaluated for brain uptake and binding by PET imaging in Danish Landrace pigs. (S)-[¹¹C]- and (R)-[¹¹C]- showed very limited brain uptake. Pre-treatment with cyclosporine A (CsA) resulted in a large increase in brain uptake, indicating that (R)-[¹¹C]- is a substrate for active efflux-transporters. This was confirmed in Madin Darby canine kidney (MDCK) cells overexpressing permeability glycoprotein (Pgp). In conclusion, the limited brain uptake of both (S)-[¹¹C]- and (R)-[¹¹C]- in the pig brain necessitates the search for alternative radioligands for in vivo PET brain imaging of ¦Á₁-adrenoceptors.