A novel β-adrenoceptor ligand for positron emission tomography: Evaluation in experimental animals

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Abstract

Myocardial and pulmonary β-adrenoceptors can be imaged and quantified with the antagonist (S)-4-[3[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-[11C]-one (S-[11C]CGP-12177). The synthesis of this ligand (based on the reaction of a precursor with [11C]phosgene) is laborious and in many centers the final product has a low and variable specific activity. This prevents widespread use of S-[11C]CGP-12177 for studies in patients. We prepared S-[11C]CGP-12388, the isopropyl analogue of CGP-12177, by a reliable one-pot procedure and evaluated the radiopharmaceutical for β-adrenoceptor imaging. Blocking experiments with subtype-selective β-adrenergic drugs showed that myocardial and pulmonary uptake of S-[11C]CGP-12388 in anesthetized rats reflects ligand binding to β1- and β2-adrenoceptors. In this animal model, clearance, metabolism and tissue/plasma ratios of S-[11C]CGP-12388 were similar to those of S-[11C]CGP-12177. A [18F]fluoroisopropyl analogue of CGP-12177 showed less favorable characteristics. S-[11C]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.

Introduction

The β-adrenoceptor antagonist (S)-4-[3[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-[11C]-one (S-[11C]CGP-12177) is suitable for β-adrenoceptor imaging. It binds with sub-nM affinity to β1- and β2-adrenoceptors (Affolter et al., 1985; Nanoff et al., 1987). Because of its hydrophilicity (log P octanol:buffer, −0.55 at pH 7.4, (Staehelin et al., 1983; Abrahamsson et al., 1988)), it labels only functional receptors at the cell surface (Hertel and Staehelin, 1983; Hertel et al., 1983; Staehelin and Hertel, 1983; Staehelin et al., 1983) and shows little nonspecific binding (Staehelin and Hertel, 1983; Staehelin et al., 1983).

CGP-12177 is labeled with carbon-11 by reaction of a diamine precursor with [11C]phosgene (Boullais et al., 1986; Hammadi and Crouzel, 1991; Aigbirhio et al., 1992a, Aigbirhio et al., 1992b). The product, S-[11C]CGP-12177, has been successfully employed for quantification of β-adrenoceptors in the myocardium of humans (Lefroy et al., 1993; Merlet et al., 1993; Choudhury et al., 1996) and dogs (Delforge et al., 1991; Delforge, 1994; Valette et al., 1995) and in human lung (Ueki et al., 1993; Qing et al., 1996a, Qing et al., 1996b). Many diseases, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, hypertension and heart failure, are associated with altered β-adrenoceptor densities or an altered coupling of β-adrenoceptors to distal 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 β-adrenoceptors are therefore of clinical interest.

Unfortunately, we and several other PET centers have experienced unusually great difficulty in the set-up of a reproducible production of S-[11C]CGP-12177. Specific activities of the radioligand are variable and usually very low. During the multi-step synthesis of [11C]phosgene from [11C]carbon dioxide, significant amounts of carrier are introduced. Protracted and systematic attempts to eradicate the source of carrier have not resulted in a reliable synthesis. Yet, reliability is essential for the clinical use of any radiopharmaceutical.

For this reason, we explored possible alternatives to S-[11C]CGP-12177. A good candidate for labeling is CGP-12388, the isopropyl analogue of CGP-12177. In functional experiments on isolated guinea pig heart and on the myocardium of the anesthetized cat, CGP-12388 is equally or slightly (<2 fold) less potent than CGP-12177 (Jaeggi et al., unpublished). Moreover, CGP-12388 is as hydrophilic as CGP-12177 (log P, −0.64). In contrast to the laborious synthesis of CGP-12177, S-[11C]CGP-12388 can be produced from [11C]acetone by a one-pot procedure (Elsinga et al., 1997).

The present study is an evaluation of this novel ligand in experimental animals. We report the results of biodistribution experiments, PET imaging, subtype-selective β-adrenoceptor blockade, tests on stereoselectivity of the binding, clearance and metabolism. In all in vivo tests, S-[11C]CGP-12388 scored comparable to S-[11C]CGP-12177 and better than another established β-adrenoceptor ligand, S-1′-[18F]fluorocarazolol (Zheng et al., 1994; Elsinga et al., 1996; Visser et al., 1997, see Fig. 1 for chemical structures). Since it can be reliably prepared, S-[11C]CGP-12388 may become the radioligand of choice for clinical studies of β-adrenoceptors.

Section snippets

Materials

S-[11C]CGP-12388 was prepared by reacting a desisopropyl precursor with [11C]acetone (Elsinga et al., 1997). Radiochemical purity of the product was >99.8% and the specific activity ranged from 22 to 30 TBq (600 to 800 Ci)/mmol. In a few experiments, the fluoroisopropyl analogue of CGP-12388 was produced by reaction of the desisopropyl precursor with [18F]fluoroacetone (Elsinga et al., 1996). The radiochemical purity of this product was also >99.8% and the average specific activity was 74 TBq

Blocking experiments with non-subtype selective drugs

The results of experiments in which rats were pretreated with non-subtype-selective β-adrenoceptor antagonists are presented in Table 1.

Treatment of the animals with RS-propranolol (a β-adrenoceptor antagonist) reduced the uptake of [11C] in heart, lungs, erythrocytes, spleen and trachea. Plasma radioactivity was increased. Cerebral uptake was minimal and the brain never accumulated radioactivity above plasma levels.

A low dose of the S(−)-isomer of propranolol was almost as effective as RS

Discussion

Because the synthesis of S-[11C]CGP-12177 from [11C]carbon dioxide via [11C]phosgene was not sufficiently reliable for clinical studies, we prepared the [11C]isopropyl- and [18F]fluoroisopropyl analogs of CGP-12177 ([11C]CGP-12388 and [18F]-fluoro-CGP-12388) and evaluated the suitability of these compounds for β-adrenoceptor imaging. During an early stage of this project, the signal-to-noise ratios of [11C]CGP-12388 were found to be superior to those of [18F]fluoro-CGP-12388. We therefore

Acknowledgements

We thank Novartis for CGP-12177, CGP-20712A and the precursor material of CGP-12388, and ICI Pharma for their gift of ICI-118,551. The expenses of this study were partially covered by a grant of the Netherlands Asthma Foundation (to T.J. Visser). P.D. was financially supported by the Netherlands Organisation for Scientific Research (NWO).

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