A new peptidic somatostatin agonist with high affinity to all five somatostatin receptors

Abstract

All commercially available somatostatin analogs for clinical use have a preference for some but not all somatostatin receptor subtypes. We describe here the synthesis and evaluation in binding and cAMP assays with cell lines stably transfected with sst₁–sst₅ of a new type of nonapeptide somatostatin analog with a reduced-sized and stabilized structure, Tyr⁰–(cyclo-d-Dab–Arg–Phe–Phe–d-Trp–Lys–Thr–Phe) (KE108). All five somatostatin receptors subtypes have an extremely high affinity for KE108, equivalent to SS-28 at sst₁ and two to four times higher than SS-28 at sst₂, sst₃, sst₄ and sst₅. Moreover, the compound has agonistic properties at all five subtypes, since it is able to inhibit the forskolin-stimulated cAMP production in sst₁–sst₅ cells. It is stable for several hours in human serum. This analog may therefore represent a considerable improvement over commercially available somatostatin analogs as it will target all somatostatin receptor subtypes, a particular advantage for cancer-related applications, as human cancers can express concomitantly several somatostatin receptor subtypes.

Introduction

In the past 20 years, several somatostatin analogs have been developed for clinical use. Unlabeled octreotide and lanreotide are being used for the symptomatic treatment of neuroendocrine tumors Lamberts et al., 1996, Oberg, 1998. More recently, ¹¹¹In- and ⁹⁰Y-labeled, chelator-bound octreotide and lanreotide have been used for the diagnosis and radiotherapy of somatostatin receptor-expressing tumors Krenning et al., 1995, Krenning et al., 1996, Otte et al., 1998, Paganelli et al., 2001, Traub et al., 2001. There are, however, at least five different somatostatin receptor subtypes (Hoyer et al., 1995), which may be expressed concomitantly and in various combinations in normal or pathological somatostatin targets Patel, 1999, Reubi et al., 2001, Schaer et al., 1997. It is therefore of prime interest to either develop analogs selective for one particular subtype (Rohrer et al., 1998), for use in restricted indications, or develop analogs that bind equally well to all five subtypes (pan-somatostatin), for broader indications and, perhaps, to take advantage of multiple somatostatin receptor subtype interactions, such as homo- and heterodimerisation Pfeiffer et al., 2001, Rocheville et al., 2000. Unfortunately, successful somatostatin analogs commercially available for clinical use have a preference for some of the somatostatin receptor subtypes (sst₂, sst₃, sst₅) but not for others (sst₁, sst₄) (Hoyer et al., 1995). The search for somatostatin analogs with a high affinity binding profile to all five subtypes was only started a few years ago. Some somatostatin analogs have been claimed to correspond almost to a pan-somatostatin, such as ¹¹¹In-1,4,7,10-tetraazadodecane 1,4,7,10-tetraacetic acid (DOTA)-lanreotide (Mauritius) (Traub et al., 2001) or depreotide (P829) (Blum et al., 2000). Binding studies with sst₁–sst₅-transfected cells have, however, revealed that these analogs still retained a low affinity for sst₁ and sst₄ subtypes (Reubi et al., 2000a) as is also the case for octreotide. In fact, when used in the clinic, compounds like ¹¹¹In-DOTA-lanreotide or ⁹⁹Tc-P829 behave only marginally differently or are considerably less adequate than the corresponding octreotide analogs Lebtahi et al., 2002, Virgolini et al., 2001. A further search for adequate pan-somatostatins was therefore indicated. In the present study, we describe a novel somatostatin analog that binds with high affinity to all five somatostatin receptor subtypes and has agonistic properties to all five subtypes.