Page 172 - Cellular Imaging in Regenerative Medicine, Cancer and Osteoarthritis

Chapter 8
has shown excellent receptor affinity and good in vivo stability. Preclinical as well as clinical PET imaging studies using [68Ga]Ga-SB3 have been performed with success (35, 36); lesions in patients were visualized in about 50 % of the cases. For radio-guided tumour detection of malignant lesions, after injection of a radiopharmaceutical a handheld detection probe is used during surgery. Combining this intra-operative method with information from pre-operative imaging will allow accurate surgical guidance, ultimately improving surgical outcome while minimizing surgical invasiveness. We wanted SB-3 to be useful for both pre-operative imaging and intra-operative radio-guided tumour detection and therefore we labelled it with Indium-111. However, after labelling with Indium-111 the molecule shows poor in vivo stability (37). Radiopeptide integrity is challenged when injected into the circulation, by omnipresent proteolytic enzymes in the bloodstream. Enzymes also reside in organs, like liver, lungs, kidneys, and gastrointestinal tract, where radiopeptides are also exposed to. A neutral endopeptidase (NEP) inhibitor, such as phosphoramidon, can inhibit the enzymatic degradation of radiopeptides (38, 39). Phosphoramidon (PA) can be injected as a bolus together with a radiopeptide (40). The in vivo stability of [111In]In-SB3 +/- PA was analysed in blood samples from mice. Radiotracer co-injected with PA showed twice as much circulating radioactivity consisting of intact radiotracer compared to that in control animals (no co-injection of PA), leading to 100% more intact tracer reaching the tumor at 1h post injection. At all-time points studied, there was significantly higher tumor uptake when PA was co-administered with [111In]In-SB3. The radiotracer uptake in the tumour was receptor-specific as concluded from the significantly decreased uptake when an excess of unlabelled SB3 was co-administered. Injection with 25 MBq/200 pmol [111In]In- SB3 +/- PA resulted in clearly improved tumour visualization with SPECT at all imaging time points when the radiotracer was combined with PA. After analysis of the images to determine the uptake of radioactivity (by drawing region of interest) an increase of 1.7 in signal intensity was shown when mice were injected with [111In]In-SB3 + PA versus control animals. So, in vivo stabilization of [111In]In-SB3 by inhibition of NEP resulted in higher tumour uptake. The radiopeptide uptake in the pancreas also increased when [111In]In-SB3 was co- administered with PA, so the tumour to pancreas ratio remained unaffected. Nevertheless, high uptake in the pancreas should be kept in mind when the radiotracer would be used for radio-guided surgery of tumor lesions close
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