Pyridyl-Ala in the third position of radiolabeled somatostatin antagonists: the effect of regioisomeric substitution

Introduction

Radiolabeled somatostatin analogs play a pivotal role in the management of neuroendocrine tumor (NET) patients due to the high expression of somatostatin receptors (SST), especially the subtype 2 (SST₂), on NET cells (Ambrosini et al. 2021). Nowadays, the SST₂ agonists [⁶⁸Ga]Ga-DOTA-TOC (⁶⁸Ga-DOTA-[Tyr³]-octreotide, where DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid) and [⁶⁸ Ga]Ga/[¹⁷⁷Lu]Lu-DOTA-TATE (⁶⁸Ga/¹⁷⁷Lu-DOTA-[Tyr³,Thr⁸]-octreotide) are approved and part of the clinical routine. These are analogs of octreotide (dPhe¹‐c(Cys²‐Phe³‐dTrp⁴-Lys⁵‐Thr⁶‐Cys⁷)-Tyr(ol)⁸), commonly substituted in position 3 by Tyr³. Over the last few years, radiolabeled octreotide-based SST₂ antagonists showed certain advantages over agonists and entered into clinical trials for imaging and treatment of NETs (Fani et al. 2017; Imperiale et al. 2023). Among these ligands, the SST₂ antagonists LM3 = Phe(4-Cl)¹‐c(dCys²‐Tyr³‐dAph(Cbm)⁴‐Lys⁵‐Thr⁶‐Cys⁷)-dTyr⁸-NH₂ (Fani et al. 2011), where dAph(Cbm) = D-4-amino-carbamoyl-phenylalanine, and JR11 = Phe(4-Cl)¹‐c(dCys²‐Aph(Hor)³‐dAph(Cbm)⁴‐Lys⁵‐Thr⁶‐Cys⁷)-dTyr⁸-NH₂ (Fani et al. 2012), where Aph(Hor) = 4-amino-L-hydroorotyl-phenylalanine, stand out due to their excellent targeting properties, i.e. high affinity and selectivity for SST₂, and optimal in vivo characteristics, such as high and persistent tumor uptake. As of today, DOTA-LM3 labeled with ¹⁷⁷Lu (Baum et al. 2021) or ¹⁶¹Tb (Fricke et al. 2024) and DOTA-JR11 labeled with ¹⁷⁷Lu (Wild et al. 2023), along with their corresponding NODAGA (1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid) conjugates labeled with ⁶⁸Ga (Nicolas et al. 2018; Lin et al. 2023; Zhu et al. 2021) and ⁶¹Cu (NCT06455358), are in the focus of clinical development as new theranostics for NETs. Clinical data on radiolabeled somatostatin receptor antagonists indicate several advantages over currently used agonists, including higher and more prolonged tumor uptake, as well as increased imaging sensitivity (Imperiale et al. 2023; Wild 2024).

The third position of the octreotide structure is involved in the critical type II’ β-turn formed by the active core Phe³‐dTrp⁴-Lys⁵‐Thr⁶. Early on, modifications of this core, demonstrated the impact of position 3 on key properties,...