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Preclinical evaluation of somatostatin analogues for breast cancer imaging using positron emission tomography. Dude, Iulia Gabriela


Somatostatin receptors (sstrs) are G-protein coupled receptors that modulate hormone secretions. Their overexpression on neuroendocrine tumours (NETs) has enabled successful imaging of these cancers with radioactive peptides using positron emission tomography. Luminal A breast cancers also overexpress sstr, but with a lower and more heterogeneous density than NETs. Recently, several authors demonstrated higher tumour binding with sstr antagonists compared to agonists. Antagonists are hypothesized to bind to target receptors in multiple configurations, thus labeling more binding sites than high-affinity agonists. This property could result in better visualization of tumours with lower sstr density, such as breast cancers. We hypothesized that the somatostatin agonist peptides TOC and TATE and antagonist peptide JR11 could be radiolabeled with ⁶⁸Ga and ¹⁸F, and that antagonist radiotracers will show higher tumour uptake when evaluated in vivo using the human breast cancer xenograft ZR-75-1. We synthesized the literature compounds ⁶⁸Ga-DOTATOC, ⁶⁸Ga-DOTATATE and antagonist ⁶⁸Ga-NODAGA-JR11 and evaluated binding affinity and tumour uptake. The agonist ⁶⁸Ga-DOTATOC had the highest tumour uptake (18.4 ± 2.87 %ID/g), and the antagonist ⁶⁸Ga-NODAGA-JR11, the lowest (12.1 ± 0.78 %ID/g). We radiolabeled the same peptide analogues with ¹⁸F using the easy and robust AmBF₃ method. ¹⁸F is an excellent isotope for peptide radiolabeling, having low positron energy (634 keV), a half-life well-matched to peptide kinetics (110 min), and an established cyclotron production method. We synthesized the compounds ¹⁸F-AmBF₃-TOC, ¹⁸F-AmBF3-TATE and ¹⁸F-AmBF3-JR11 and found that all were kinetically stable (determined by in vivo plasma stability studies) and successfully visualized the tumour with high intensity and contrast at both 1 hour and 2 hours post-injection (p.i.). At 1 h p.i. uptake means were between 10.0 – 13.4 %ID/g for all three radiotracers, and differences were not statistically significant. Imaging with ¹⁸F- and ⁶⁸Ga-labeled JR11 antagonists did not confer any additional advantages compared to agonists in this tumour model. However, the high tumour uptake of both ⁶⁸Ga- and ¹⁸F-labeled antagonists is striking, despite their significantly poorer binding affinity (inhibition contrast (Ki) > 18 nM) compared to agonist (Ki < 1.5 nM). With modifications to improve affinity, antagonist somatostatin analogues may be very promising for breast cancer visualization.

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