Radiolabelling and PET brain imaging of the a1-adrenoceptor antagonist Lu AE43936

Rune Risgaard; Anders Janusz Ettrup; Thomas Balle; Agnete Dyssegaard; Hanne Demant Hansen; Szabolcs Lehel; Jacob Madsen; Henrik Pedersen; Ask Püschl; Lassina Badolo; Benny Bang-Andersen; Gitte Moos Knudsen; Jesper Langgaard Kristensen

doi:10.1016/j.nucmedbio.2012.09.010

Radiolabelling and PET brain imaging of the a1-adrenoceptor antagonist Lu AE43936

Rune Risgaard, Anders Janusz Ettrup, Thomas Balle, Agnete Dyssegaard, Hanne Demant Hansen, Szabolcs Lehel, Jacob Madsen, Henrik Pedersen, Ask Püschl, Lassina Badolo, Benny Bang-Andersen, Gitte Moos Knudsen, Jesper Langgaard Kristensen

14 Citations (Scopus)

Abstract

Cerebral α₁-adrenoceptors are a common target for many antipsychotic drugs. Thus, access to positron emission tomography (PET) brain imaging of α₁-adrenoceptors could make important contributions to the understanding of psychotic disorders as well as to the pharmacokinetics and occupancy of drugs targeting the α₁-adrenoceptors. However, so far no suitable PET radioligand has been developed for brain imaging of α₁-adrenoceptors. Here, we report the synthesis of both enantiomers of the desmethyl precursors of the high affinity α₁-adrenoceptor ligand Lu AE43936 (1). The two enantiomers of 1 were subsequently [¹¹C] radiolabelled and evaluated for brain uptake and binding by PET imaging in Danish Landrace pigs. (S)-[¹¹C]-1 and (R)-[¹¹C]-1 showed very limited brain uptake. Pre-treatment with cyclosporine A (CsA) resulted in a large increase in brain uptake, indicating that (R)-[¹¹C]-1 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]-1 and (R)-[¹¹C]-1 in the pig brain necessitates the search for alternative radioligands for in vivo PET brain imaging of α₁-adrenoceptors.

Original language	English
Journal	Nuclear Medicine & Biology
Volume	40
Issue number	1
Pages (from-to)	135-140
Number of pages	6
DOIs	https://doi.org/10.1016/j.nucmedbio.2012.09.010
Publication status	Published - Jan 2013

Access to Document

10.1016/j.nucmedbio.2012.09.010

Cite this

Risgaard, R., Ettrup, A. J., Balle, T., Dyssegaard, A., Hansen, H. D., Lehel, S., Madsen, J., Pedersen, H., Püschl, A., Badolo, L., Bang-Andersen, B., Knudsen, G. M., & Kristensen, J. L. (2013). Radiolabelling and PET brain imaging of the a1-adrenoceptor antagonist Lu AE43936. Nuclear Medicine & Biology, 40(1), 135-140. https://doi.org/10.1016/j.nucmedbio.2012.09.010

@article{67ccb380a4b04263a35d6b24645e30a2,

title = "Radiolabelling and PET brain imaging of the a1-adrenoceptor antagonist Lu AE43936",

abstract = "Cerebral α1-adrenoceptors are a common target for many antipsychotic drugs. Thus, access to positron emission tomography (PET) brain imaging of α1-adrenoceptors could make important contributions to the understanding of psychotic disorders as well as to the pharmacokinetics and occupancy of drugs targeting the α1-adrenoceptors. However, so far no suitable PET radioligand has been developed for brain imaging of α1-adrenoceptors. Here, we report the synthesis of both enantiomers of the desmethyl precursors of the high affinity α1-adrenoceptor ligand Lu AE43936 (1). The two enantiomers of 1 were subsequently [11C] radiolabelled and evaluated for brain uptake and binding by PET imaging in Danish Landrace pigs. (S)-[11C]-1 and (R)-[11C]-1 showed very limited brain uptake. Pre-treatment with cyclosporine A (CsA) resulted in a large increase in brain uptake, indicating that (R)-[11C]-1 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]-1 and (R)-[11C]-1 in the pig brain necessitates the search for alternative radioligands for in vivo PET brain imaging of α1-adrenoceptors.",

author = "Rune Risgaard and Ettrup, {Anders Janusz} and Thomas Balle and Agnete Dyssegaard and Hansen, {Hanne Demant} and Szabolcs Lehel and Jacob Madsen and Henrik Pedersen and Ask P{\"u}schl and Lassina Badolo and Benny Bang-Andersen and Knudsen, {Gitte Moos} and Kristensen, {Jesper Langgaard}",

year = "2013",

month = jan,

doi = "10.1016/j.nucmedbio.2012.09.010",

language = "English",

volume = "40",

pages = "135--140",

journal = "Nuclear Medicine and Biology",

issn = "0969-8051",

publisher = "Elsevier",

number = "1",

}

TY - JOUR

T1 - Radiolabelling and PET brain imaging of the a1-adrenoceptor antagonist Lu AE43936

AU - Risgaard, Rune

AU - Ettrup, Anders Janusz

AU - Balle, Thomas

AU - Dyssegaard, Agnete

AU - Hansen, Hanne Demant

AU - Lehel, Szabolcs

AU - Madsen, Jacob

AU - Pedersen, Henrik

AU - Püschl, Ask

AU - Badolo, Lassina

AU - Bang-Andersen, Benny

AU - Knudsen, Gitte Moos

AU - Kristensen, Jesper Langgaard

PY - 2013/1

Y1 - 2013/1

N2 - Cerebral α1-adrenoceptors are a common target for many antipsychotic drugs. Thus, access to positron emission tomography (PET) brain imaging of α1-adrenoceptors could make important contributions to the understanding of psychotic disorders as well as to the pharmacokinetics and occupancy of drugs targeting the α1-adrenoceptors. However, so far no suitable PET radioligand has been developed for brain imaging of α1-adrenoceptors. Here, we report the synthesis of both enantiomers of the desmethyl precursors of the high affinity α1-adrenoceptor ligand Lu AE43936 (1). The two enantiomers of 1 were subsequently [11C] radiolabelled and evaluated for brain uptake and binding by PET imaging in Danish Landrace pigs. (S)-[11C]-1 and (R)-[11C]-1 showed very limited brain uptake. Pre-treatment with cyclosporine A (CsA) resulted in a large increase in brain uptake, indicating that (R)-[11C]-1 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]-1 and (R)-[11C]-1 in the pig brain necessitates the search for alternative radioligands for in vivo PET brain imaging of α1-adrenoceptors.

AB - Cerebral α1-adrenoceptors are a common target for many antipsychotic drugs. Thus, access to positron emission tomography (PET) brain imaging of α1-adrenoceptors could make important contributions to the understanding of psychotic disorders as well as to the pharmacokinetics and occupancy of drugs targeting the α1-adrenoceptors. However, so far no suitable PET radioligand has been developed for brain imaging of α1-adrenoceptors. Here, we report the synthesis of both enantiomers of the desmethyl precursors of the high affinity α1-adrenoceptor ligand Lu AE43936 (1). The two enantiomers of 1 were subsequently [11C] radiolabelled and evaluated for brain uptake and binding by PET imaging in Danish Landrace pigs. (S)-[11C]-1 and (R)-[11C]-1 showed very limited brain uptake. Pre-treatment with cyclosporine A (CsA) resulted in a large increase in brain uptake, indicating that (R)-[11C]-1 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]-1 and (R)-[11C]-1 in the pig brain necessitates the search for alternative radioligands for in vivo PET brain imaging of α1-adrenoceptors.

U2 - 10.1016/j.nucmedbio.2012.09.010

DO - 10.1016/j.nucmedbio.2012.09.010

M3 - Journal article

C2 - 23165140

SN - 0969-8051

VL - 40

SP - 135

EP - 140

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

IS - 1

ER -

Radiolabelling and PET brain imaging of the a1-adrenoceptor antagonist Lu AE43936

Abstract

Access to Document

Fingerprint

Cite this