Design of new beta1-selective adrenoceptor ligands as potential radioligands for in vivo imaging.
In general, the failing human heart is characterized by a selective reduction in beta(1)-adrenoceptors (beta(1)-ARs) without change in beta(2)-AR density. Medical imaging techniques, either single photon emission computed tomography (SPECT) or positron emission tomography (PET) with appropriate radioligands, offer the possibility of assessing beta-adrenoceptor density non-invasively in humans. To date, neither a SPECT nor a PET radioligand is available for the selective imaging of cardiac beta(1)-ARs. The aim of this study was to develop potential high affinity beta(1)-selective AR radioligands for the non-invasive in vivo imaging of the beta(1)-AR density in the human heart using SPECT or PET. A variety of racemic N-aryl-N'-[2-[3-aryloxy-2-hydroxy-propylamino]-ethyl]-urea derivatives and chain-elongated analogues, related to the established beta(1)-AR antagonist, ICI 89,406 8i, were synthesized. Competition studies using the non-selective AR ligand, [(125)I]iodocyanopindolol ([(125)I]ICYP), and ventricular membrane preparations of wild-type mice revealed nine ligands with higher beta(1)-AR affinities (up to 76-fold) and beta(1)-AR selectivities (up to 139-fold) than 8i. Mostly, these ligands possess a 2-substituted phenoxy group and a 4-substituted phenyl residue in contrast to the lead compound 8i. The non-radioactive counterparts of the desired SPECT- and PET-radiotracers were synthesized as reference compounds [e.g., 8f, 8g, 8h and 8l as the non-radioactive analogues of the radioiodinated SPECT radioligands, 8e and 8h as the non-radioactive compounds of C-11 labelled PET-tracers (C-11 in the methoxy group)]. The established library of high affinity beta(1)-selective AR antagonists was screened for chemical precursors for the radiosynthesis of the mentioned radioligands. Furthermore, the library consists of some comparison compounds that are unsubstituted, allyl- and alkyl-substituted or chain-elongated (e.g., 8a, 8j, 8o and 8r-t). Future steps will include radiolabelling and pharmacokinetic evaluation of the beta(1)-selective target compounds, which could be applied as sympathetic innervation agents for in vivo investigations and diagnostics in patients suffering from cardiac diseases like heart failure and ventricular arrhythmias.
Kopka
Klaus
K
Department of Nuclear Medicine, Albert-Schweitzer-Str. 33, University Hospital Münster, 48149, Münster, Germany. kopka@uni-muenster.de
Wagner
Stefan
S
Riemann
Burkhard
B
Law
Marilyn P
MP
Puke
Carsten
C
Luthra
Sajinder K
SK
Pike
Victor W
VW
Wichter
Thomas
T
Schmitz
Wilhelm
W
Schober
Otmar
O
Schäfers
Michael
M
D058671:Adrenergic beta-1 Receptor Antagonists; D000818:Animals; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D020120:Iodocyanopindolol / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D009206:Myocardium / Q000378:metabolism; D011412:Propanolamines / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay / Q000379:methods*; D018342:Receptors, Adrenergic, beta-1 / Q000032:analysis* / Q000378:metabolism*; D013379:Substrate Specificity; D013997:Time Factors; D014055:Tomography, Emission-Computed; D015899:Tomography, Emission-Computed, Single-Photon
D058671:Adrenergic beta-1 Receptor Antagonists; D008024:Ligands; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D020120:Iodocyanopindolol; C025716:ICI 89406