Somatostatin receptor PET ligands - the next generation for clinical practice

Somatostatin receptors (SSTRs) are variably expressed by a variety of malignancies. Using radiolabeled somatostatin analogs (SSAs), the presence of SSTRs on tumor cells may be exploited for molecular imaging and for peptide receptor radionuclide therapy. ¹¹¹In-DTPA-octreotide has long been the standard in SSTR scintigraphy. A major leap forward was the introduction of gallium-68 labeled SSAs for positron emission tomography (PET) offering improved sensitivity. Tracers currently in clinical use are ⁶⁸Ga-DOTA-Tyr³-octreotide (⁶⁸Ga-DOTATOC), ⁶⁸Ga-DOTA-Tyr³-octreotate (⁶⁸Ga-DOTATATE) and ⁶⁸Ga-DOTA-1-NaI³-octreotide (⁶⁸Ga-DOTANOC), collectively referred to as ⁶⁸Ga-DOTA-peptides. ⁶⁸Ga-DOTA-peptide PET has superseded ¹¹¹In-DTPA-octreotide scintigraphy as the modality of choice for SSTR imaging. However, implementation of ⁶⁸Ga-DOTA-peptides in routine clinical practice is often limited by practical, economical and regulatory factors related to the use of the current generation of ⁶⁸Ge/⁶⁸Ga generators. Centralized production and distribution is challenging due to the low production yield and relatively short half-life of gallium-68. Furthermore, gallium-68 has a relatively long positron range, compromising spatial resolution on modern PET cameras. Therefore, possibilities of using other PET radionuclides are being explored. On the other hand, new developments in SSTR PET ligands are strongly driven by the need for improved lesion targeting, especially for tumors with low SSTR expression. This may be achieved by using peptide vectors having a higher affinity for the SSTR or a broader affinity profile for the different receptor subtypes or by using compounds recognizing more binding sites, such as SSTR antagonists. This review gives an overview of recent developments leading to the next generation of clinical PET tracers for SSTR imaging.