Affinity profiles for human somatostatin receptor subtypes SST1–SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use
Abstract
In vivo somatostatin receptor scintigraphy using Octreoscan is a valuable method for the visualisation of human endocrine tumours and their metastases. Recently, several new, alternative somatostatin radioligands have been synthesised for diagnostic and radiotherapeutic use in vivo. Since human tumours are known to express various somatostatin receptor subtypes, it is mandatory to assess the receptor subtype affinity profile of such somatostatin radiotracers. Using cell lines transfected with somatostatin receptor subtypes sst1, sst2, sst3, sst4 and sst5, we have evaluated the in vitro binding characteristics of labelled (indium, yttrium, gallium) and unlabelled DOTA-[Tyr3]-octreotide, DOTA-octreotide, DOTA-lanreotide, DOTA-vapreotide, DTPA-[Tyr3]-octreotate and DOTA-[Tyr3]-octreotate. Small structural modifications, chelator substitution or metal replacement were shown to considerably affect the binding affinity. A marked improvement of sst2 affinity was found for Ga-DOTA-[Tyr3]-octreotide (IC50 2.5 nM) compared with the Y-labelled compound and Octreoscan. An excellent binding affinity for sst2 in the same range was also found for In-DTPA-[Tyr3]-octreotate (IC50 1.3 nM) and for Y-DOTA-[Tyr3]-octreotate (IC50 1.6 nM). Remarkably, Ga-DOTA-[Tyr3]-octreotate bound at sst2 with a considerably higher affinity (IC50 0.2 nM). An up to 30-fold improvement in sst3 affinity was observed for unlabelled or Y-labelled DOTA-octreotide compared with their Tyr3-containing analogue, suggesting that replacement of Tyr3 by Phe is crucial for high sst3 affinity. Substitution in the octreotide molecule of the DTPA by DOTA improved the sst3 binding affinity 14-fold. Whereas Y-DOTA-lanreotide had only low affinity for sst3 and sst4, it had the highest affinity for sst5 among the tested compounds (IC50 16 nM). Increased binding affinity for sst3 and sst5 was observed for DOTA-[Tyr3]-octreotide, DOTA-lanreotide and DOTA-vapreotide when they were labelled with yttrium. These marked changes in subtype affinity profiles are due not only to the different chemical structures but also to the different charges and hydrophilicity of these compounds. Interestingly, even the coordination geometry of the radiometal complex remote from the pharmacophoric amino acids has a significant influence on affinity profiles as shown with Y-DOTA versus Ga-DOTA in either [Tyr3]-octreotide or [Tyr3]-octreotate. Such changes in sst affinity profiles must be identified in newly designed radiotracers used for somatostatin receptor scintigraphy in order to correctly interpret in vivo scintigraphic data. These observations may represent basic principles relevant to the development of other peptide radioligands.
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DOTA-TATE exhibits high affinity for human SSTR2 (IC50 of 1.5 ± 0.4 nM) with much less binding affinity for all other human SSTRs.
“DOTA-TATE exhibits high affinity for human SSTR2 (IC50 of 1.5 ± 0.4 nM) with much less binding affinity for all other human SSTRs.”
From Lutathera®: The First FDA- and EMA-Approved Radiopharmaceutical for Peptide Receptor Radionuclide Therapy (2019) · cites this paper as [29]
Complexing DOTA-TATE with gallium results in an even higher affinity for SSTR2 (IC50 of 0.2 ± 0.04 nM).
“complexing with gallium in an even higher affinity for SSTR2 (IC50 of 0.2 ± 0.04 nM).”
From Lutathera®: The First FDA- and EMA-Approved Radiopharmaceutical for Peptide Receptor Radionuclide Therapy (2019) · cites this paper as [29]
Complexing DOTA-TATE with yttrium results in a comparable binding affinity profile to uncomplexed DOTA-TATE.
“Complexing this peptide with yttrium resulted in a comparable binding affinity profile”
From Lutathera®: The First FDA- and EMA-Approved Radiopharmaceutical for Peptide Receptor Radionuclide Therapy (2019) · cites this paper as [29]
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- Authors
- Reubi, J. C., Schär, J.-C., Waser, B., Wenger, S., Heppeler, A., Schmitt, J. S., & Mäcke, H. R.
- Affiliations
- University of Bern (CH)
- University Hospital of Basel (CH)
- Venue
- European Journal of Nuclear Medicine and Molecular Imaging
- Published
- 2000-03-07
- Volume
- 27
- Issue
- 3
- Pages
- 273-282
- ISSN
- 1619-7070 (ISSN-L)
- 1619-7089
- OpenAlex
- W2005674134
- Cited by
- 1,127
- References
- 23
- Citations by year
- 2026: 20 · 2025: 39 · 2024: 47 · 2023: 45 · 2022: 60 · 2021: 61 · 2020: 46 · 2019: 34 · 2018: 31 · 2017: 58 · 2016: 50 · 2015: 62 · 2014: 48 · 2013: 38 · 2012: 61
- FWCI
- 21.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Nuclear Medicine and Molecular Imaging (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Neuroendocrine Tumor Research Advances
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- somatostatin receptor subtypes, lanreotide, vapreotide, indium-111, somatostatin receptor scintigraphy, endocrine tumors, receptor binding affinity, sST2
- MeSH terms
- Animals, Autoradiography, Binding, Competitive, Humans, Peptides, Cyclic, Somatostatin, Octreotide, In Situ Hybridization, Receptors, Somatostatin, Radiopharmaceuticals, Rats
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