European Nuclear Medicine Guide
Somatostatin receptors (SSTRs), especially subtype SSTR2, are typically overexpressed in well-differentiated neuroendocrine tumours (NETs), making them an attractive target for imaging and radiopharmaceutical therapy with radiolabelled octreotide derivatives. Traditional molecular imaging with SSTR agonists, such as 68Ga-DOTA-TATE and 68Ga-DOTA-TOC, has been effective in evaluating the extent of disease in patients with NETs and in assessing candidacy for treatment with cold and radiolabelled octreotide analogues, according to the theranostic principle of “seeing and treating”. However, the intense liver uptake typical of imaging with SSTR agonists diminishes the ability to detect small lesions and lesions with moderate uptake in the liver. This is quite remarkable for a disease which metastasizes to the liver in over 90% of cases. Somatostatin receptor antagonists were introduced in clinical research in the 2010s owing to their ability to additionally bind inactive SSTR2 on the cell membrane, thus leading to lower overall receptor internalization [1–3]. The increased SSTR2 binding translates into better image contrast and in the detection of more lesions, particularly in the liver and spleen, as demonstrated by initial trials with 111In-labelled peptides (DOTA-BASS) [4].
The clear advantage of this class of somatostatin analogues led to the development of agents capable of being labelled with radiometals such as Ga-68 and Lu-177 for theranostic purposes. Of these, JR11 represents the first generation of SSTR antagonists for theranostics use. A pilot trial comparing the SSTR agonist 177Lu-DOTATATE and the antagonist 177Lu-DOTA-JR11 in 4 patients demonstrated significantly increased tumour accumulation of the latter and, consequently, a 1.7–10.6 times higher tumour dose [5]. From the diagnostic point of view, studies have shown that imaging with the perfected agent 68Ga-NODAGA-JR11 provided better sensitivity as well as a higher target-to-background ratio in the liver compared to 68Ga-DOTATOC and 68Ga-DOTATATE [6, 7]. However, first-generation antagonists like JR11 may have limitations in certain aspects of their pharmacokinetic profiles, which is particularly apparent when using the therapeutic counterpart. A phase 1 study that included 20 heavily treated patients with advanced SSTR2 positive NETs showed promise for treatment with 7.4 GBq of 177Lu-DOTA-JR11 (or satoreotide tetraxetan), with high radiation doses to tumours and a favourable tumour-to-normal organ dose ratio. A median progression-free survival of 21.0 months and a disease control rate (DCR) of 85% were achieved. However, an unexpected high rate of prolonged grade 3 and 4 haematological toxicity was noted after the second cycle, suggesting that a reduced treatment dose of this agent may be warranted [8]. In a phase I/II study by Wild et al., 40 patients with previously treated, progressive NETs were treated with 177Lu-DOTA-JR11 at various administered activities and peptide masses. The excellent tumour response (94.7% DCR) was hampered by a 42.5% grade 3 and 4 haematotoxicity. The authors thus recommended the administration of 13 GBq in 3 cycles, to avoid severe haematological toxicity while achieving a therapeutic benefit comparable to that of PRRT agonists but in fewer cycles and with less? cumulative activity. In the same study, there was a 5% incidence of treatment-associated myeloid malignancies, which is slightly higher than that seen with agonist PRRT. However, long-term follow up is needed to evaluate the true risk [9].
Given the relatively narrow therapeutic window due to haematological toxicity, a new generation of SSTR antagonists has been developed, including LM3 and LM4. These antagonists are often designed with improved targeting moieties and chelators, resulting in enhanced pharmacokinetic properties. The development of new hybrid chelators and modified peptides has further enhanced the pharmacokinetic properties and tumour-targeting capabilities of SSTR antagonists. For example, the DATA5m chelator has been successfully conjugated with the SSTR antagonist LM4 and labelled with 68Ga, showing high yield and purity and significantly lower uptake in normal liver parenchyma compared to 68Ga-DOTA-TATE, resulting in high tumour contrast [10]. Similarly, 18F-AlF-NOTA-LM3 exhibits excellent in vivo stability, high tumour uptake, and superior tumour-to-background ratios compared to the agonist 68Ga-DOTATATE [11].
These advancements in antagonist design, moving from first-generation agents like JR11 to newer ones like LM3 and LM4, underscore the ongoing efforts to optimize SSTR-targeted radiopharmaceuticals and ultimately increase the dose to tumours while decreasing the dose to the normal organs. From the therapeutic standpoint, second-generation SSTR antagonists have shown a better tolerability profile. Baum et al. treated 51 patients with advanced metastatic NET with the antagonist 177Lu-DOTA-LM3 while using 68Ga-NODAGA-LM3 PET/CT for patient selection and follow-up. Higher uptake and a longer effective half-life were found compared to 177Lu-DOTATOC in normal organs and tumours, which led to a DCR of 85.1%. Treatment was well tolerated, with grade 3 thrombocytopenia occurring in only a few patients. No grade 4 haematological toxicities were reported; however, the rate of severe haematological toxicity was higher than that reported for PRRT agonists, which might be related to this being a retreatment after prior PRRT, or possibly to the recruitment of a larger number of SSTR2 expressed by the haematopoietic stem cells. Of note is the fact that no nephrotoxicity was observed, despite the higher renal absorbed dose seen with SSTR antagonists[12].
Binding to somatostatin receptors, subtype 2.
Imaging and therapy of metastatic neuroendocrine tumours. Potential additional indications for high-grade neuroendocrine malignancies, hepatocellular carcinoma, metastatic breast cancer.
Alpha-PRRT – In preclinical studies, 149Tb-labelled SSTR antagonists have also shown promise [13]. Terbium-149, a short-lived α-particle emitter, has been investigated in combination with the SSTR antagonist DOTA-LM3, demonstrating effective reduction of tumour cell viability in vitro and tumour growth in mice. The radiolabelling of peptides with 149Tb was achieved with high molar activities and radiochemical purity. However, both 149Tb-DOTATATE and 149Tb-DOTA-LM3 showed similar DNA damage in AR42J tumour cells [13]. These findings suggest that alpha-PRRT, with either agonists or antagonists, can effectively target and reduce tumour growth, supporting further preclinical and clinical evaluation. Further studies need to clarify the impact of a larger SSTR recruitment with alpha emitters in preclinical and clinical models.
Leveraging SSTR expression in other diseases - The shift from agonists to antagonists is also driven by the understanding that antagonists may offer a more effective way to target tumours with lower SSTR expression. This is particularly relevant in cancers that may express lower and/or heterogeneous densities of SSTR, like small cell lung cancer, hepatocellular carcinoma, and metastatic breast cancer. In these cases, the enhanced binding affinity and reduced internalization of antagonists can lead to improved accumulation of the radiopharmaceutical in tumour tissues.