Ž . European Journal of Pharmacology 343 1998 289–296 A novel b-adrenoceptor ligand for positron emission tomography: Evaluation in experimental animals Aren van Waarde a, ) , Philip H. Elsinga a , Petra Doze a , Marco Heldoorn a , Knut A. Jaeggi b , Willem Vaalburg a a ( ) Positron Emission Tomography PET Center, UniÕersity Hospital, P.O. Box 30001, 9700 RB Groningen, The Netherlands b Pharmaceuticals DiÕision, NoÕartis AG, Basle, Switzerland Received 21 August 1997; revised 6 November 1997; accepted 14 November 1997 Abstract Ž. wwŽ . x Myocardial and pulmonary b-adrenoceptors can be imaged and quantified with the antagonist S -4- 3 1,1-dimethylethyl amino -2- x w 11 x Ž w 11 x . Ž hydroxypropoxy -1,3-dihydro-2H-benzimidazol-2- C -one S- C CGP-12177 . The synthesis of this ligand based on the reaction of a w 11 x . precursor with C phosgene is laborious and in many centers the final product has a low and variable specific activity. This prevents w 11 x w 11 x widespread use of S- C CGP-12177 for studies in patients. We prepared S- C CGP-12388, the isopropyl analogue of CGP-12177, by a reliable one-pot procedure and evaluated the radiopharmaceutical for b-adrenoceptor imaging. Blocking experiments with subtype- w 11 x selective b-adrenergic drugs showed that myocardial and pulmonary uptake of S- C CGP-12388 in anesthetized rats reflects ligand w 11 x binding to b - and b -adrenoceptors. In this animal model, clearance, metabolism and tissuerplasma ratios of S- C CGP-12388 were 1 2 w 11 x w 18 x w 11 x similar to those of S- C CGP-12177. A F fluoroisopropyl analogue of CGP-12177 showed less favorable characteristics. S- C CGP- 12388 was therefore selected for evaluation in humans and it may become the tracer of choice for clinical studies since it is easily prepared. q 1998 Elsevier Science B.V. Ž . Keywords: b-Adrenoceptor; PET positron emission tomography ; Lung; Heart; CGP-12177; CGP-12388 1. Introduction Ž. wwŽ The b-adrenoceptor antagonist S -4- 3 1,1-dimethyl- . x x ethyl amino -2-hydroxypropoxy -1,3-dihydro-2H-benzimi- w 11 x Ž w 11 x . dazol-2- C -one S- C CGP-12177 is suitable for b- adrenoceptor imaging. It binds with sub-nM affinity to b - 1 Ž and b -adrenoceptors Affolter et al., 1985; Nanoff et al., 2 . Ž 1987 . Because of its hydrophilicity log P octanol:buffer, Ž y0.55 at pH 7.4, Staehelin et al., 1983; Abrahamsson et .. al., 1988 , it labels only functional receptors at the cell Ž surface Hertel and Staehelin, 1983; Hertel et al., 1983; . Staehelin and Hertel, 1983; Staehelin et al., 1983 and Ž shows little nonspecific binding Staehelin and Hertel, . 1983; Staehelin et al., 1983 . CGP-12177 is labeled with carbon-11 by reaction of a w 11 x Ž diamine precursor with C phosgene Boullais et al., 1986; Hammadi and Crouzel, 1991; Aigbirhio et al., . w 11 x 1992a,b . The product, S- C CGP-12177, has been suc- ) Corresponding author. Tel.: q31-50-3613215; fax: q31-50-3611687. cessfully employed for quantification of b-adrenoceptors Ž in the myocardium of humans Lefroy et al., 1993; Merlet . Ž et al., 1993; Choudhury et al., 1996 and dogs Delforge et . al., 1991; Delforge, 1994; Valette et al., 1995 and in Ž . human lung Ueki et al., 1993; Qing et al., 1996a,b . Many diseases, such as asthma, chronic obstructive pulmonary Ž . disease COPD , cystic fibrosis, hypertension and heart failure, are associated with altered b-adrenoceptor densi- ties or an altered coupling of b-adrenoceptors to distal Ž parts of the transduction chain Bristow et al., 1986; Raaijmakers et al., 1987; Sharma and Jeffery, 1990; Lopes . et al., 1991; Bai et al., 1992 . PET studies of pulmonary and myocardial b-adrenoceptors are therefore of clinical interest. Unfortunately, we and several other PET centers have experienced unusually great difficulty in the set-up of a w 11 x reproducible production of S- C CGP-12177. Specific activities of the radioligand are variable and usually very w 11 x low. During the multi-step synthesis of C phosgene w 11 x from C carbon dioxide, significant amounts of carrier 0014-2999r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved.