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Published on: January 7, 2019
Macrocyclic chelator-coupled gastrin-based radiopharmaceuticals for targeting of gastrin receptor-expressing tumours
Stephan Good1, Martin A Walter, Beatrice Waser
1Division of Radiological Chemistry, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
Purpose:
Diethylenetriamine-pentaacetic acid (DTPA)-coupled minigastrins are unsuitable for therapeutic application with the available beta-emitting radiometals due to low complex stability. Low tumour-to-kidney ratio of the known radiopharmaceuticals is further limiting their potency. We used macrocyclic chelators for coupling to increase complex stability, modified the peptide sequence to enhance radiolytic stability and studied tumour-to-kidney ratio and metabolic stability using (111)In-labelled derivatives.
Methods:
Gastrin derivatives with decreasing numbers of glutamic acids were synthesised using (111)In as surrogate for therapeutic radiometals for in vitro and in vivo studies. Gastrin receptor affinities of the (nat)In-metallated compounds were determined by receptor autoradiography using (125)I-CCK as radioligand. Internalisation was evaluated in AR4-2J cells. Enzymatic stability was determined by incubating the (111)In-labelled peptides in human serum. Biodistribution was performed in AR4-2J-bearing Lewis rats.
Results:
IC(50) values of the (nat)In-metallated gastrin derivatives vary between 1.2 and 4.8 nmol/L for all methionine-containing derivatives. Replacement of methionine by norleucine, isoleucine, methionine-sulfoxide and methionine-sulfone resulted in significant decrease of receptor affinity (IC(50) between 9.9 and 1,195 nmol/L). All cholecystokinin receptor affinities were >100 nmol/L. All (111)In-labelled radiopeptides showed receptor-specific internalisation. Serum mean-life times varied between 2.0 and 72.6 h, positively correlating with the number of Glu residues. All (111)In-labelled macrocyclic chelator conjugates showed higher tumour-to-kidney ratios after 24 h (0.37-0.99) compared to (111)In-DTPA-minigastrin 0 (0.05). Tumour wash out between 4 and 24 h was low. Imaging studies confirmed receptor-specific blocking of the tumour uptake.
Conclusions:
Reducing the number of glutamates increased tumour-to-kidney ratio but resulted in lower metabolic stability. The properties of the macrocyclic chelator-bearing derivatives make them potentially suitable for clinical purposes.
Insights
Macrocyclic chelators improve radiopharmaceutical stability and tumor targeting. Modified gastrin derivatives show enhanced tumor-to-kidney ratios, suggesting potential for clinical applications in targeted radionuclide therapy.
Area of Science:
- Radiopharmaceutical chemistry
- Nuclear medicine
- Peptide chemistry
Background:
- Diethylenetriamine-pentaacetic acid (DTPA)-coupled minigastrins have limited therapeutic use due to poor complex stability and low tumor-to-kidney ratios.
- Improving radiometal complex stability and metabolic stability is crucial for effective targeted radionuclide therapy.
Purpose of the Study:
- To develop novel gastrin derivatives with enhanced complex stability and improved tumor-to-kidney ratios for therapeutic applications.
- To evaluate the impact of macrocyclic chelators and peptide modifications on radiolytic and metabolic stability.
- To assess the in vitro and in vivo performance of (111)In-labeled gastrin derivatives.
Main Methods:
- Synthesis of gastrin derivatives with varying glutamic acid content, coupled to macrocyclic chelators.
- In vitro evaluation of gastrin receptor affinity and cellular internalization in AR4-2J cells.
- In vivo biodistribution studies in AR4-2J-bearing Lewis rats using (111)In-labeled peptides.
- Assessment of metabolic stability by incubation in human serum.
Main Results:
- (nat)In-metallated gastrin derivatives exhibited high gastrin receptor affinity (IC50: 1.2–4.8 nmol/L).
- (111)In-labeled macrocyclic chelator conjugates demonstrated significantly higher tumor-to-kidney ratios (0.37–0.99 at 24h) compared to (111)In-DTPA-minigastrin (0.05).
- Metabolic stability varied, with longer serum half-lives correlating with increased glutamic acid residues, while reduced glutamates improved tumor-to-kidney ratios.
Conclusions:
- Reducing glutamate residues enhances tumor-to-kidney ratios but decreases metabolic stability.
- Macrocyclic chelator-bearing gastrin derivatives show promising properties for clinical application in targeted radionuclide therapy.
- Further optimization is needed to balance metabolic stability and tumor targeting efficacy.
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