Page 104 - Cellular Imaging in Regenerative Medicine, Cancer and Osteoarthritis

Chapter 5
Abstract
Purpose
The gastrin releasing peptide receptor (GRPR), overexpressed on various tumor types, is an attractive target for receptor-mediated imaging & therapy. Another interesting approach would be the use of GRPR radioligands for pre-operative imaging and subsequent radio-guided surgery, with the goal to improve surgical outcome. GRPR radioligands were successfully implemented in clinical studies, especially Sarabesin 3 (SB3) is an appealing GRPR antagonist with high receptor affinity. Gallium-68 (68Ga) labelled SB3 has good in vivo stability, after labeling with Indium-111 (111In) however, the molecule shows poor in vivo stability, which negatively impacts tumor targeting capacity. A novel approach to increase in vivo stability of radiopeptides is by co-administration of the neutral endopeptidase (NEP) inhibitor, phosphoramidon (PA). We studied in vivo stability and biodistribution of [111In]SB3 without/with (-/+) PA in mice. Furthermore, SPECT/MRI on a novel, state-of-the-art platform was performed.
Procedures
GRPR-affinity of SB3 was determined on PC295 xenograft sections using [125I] Tyr4-bombesin with tracer only or with increasing concentrations of SB3. For in vivo stability, mice were injected with 200/2000 pmol [111In]SB3 -/+ 300 μg PA. Blood was collected and analyzed. Biodistribution and SPECT/MRI studies were performed at 1, 4 and 24 h post injection (p.i.) of 2.5 MBq/200 pmol or 25 MBq/200 pmol [111In]SB3 -/+ 300 μg PA in PC-3-xenografted mice.
Results
SB3 showed high affinity for GRPR (IC50: 3.5 nM). Co-administration of PA resulted in twice higher intact peptide in vivo versus [111In]SB3 alone. Biodistribution studies at 1, 4 and 24 h pi. show higher tumor uptake values with PA co-administration (19.7±3.5 vs 10.2±1.5, 17.6±5.1 vs 8.3±1.1, 6.5±3.3 vs 3.1±1.9 %ID/g tissue (P<0.0001)). Tumor imaging with SPECT/MRI clearly improved after co-injection of PA.
Conclusions
Co-administration of PA increased in vivo tumor targeting capacity of [111In] SB3, making this an attractive combination for GRPR-targeted tumor imaging.
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