Page 107 - Cellular Imaging in Regenerative Medicine, Cancer and Osteoarthritis

Stabilized Sarabesin-3 for prostate imaging
parathyroid adenomas [14-18]. Multiple radiopharmaceuticals and administration methods are applied for radio-guided surgery amongst which the application of systemically administered radiopharmaceuticals directed against targets that are overexpressed on tumor cells. Examples include ongoing preclinical and (pilot) patient studies evaluating the potential benefits of radio-guided surgery for the detection of neuroendocrine tumor and prostate cancer lesions using somatostatin receptor-targeting and prostate- specific membrane antigen-targeting radiotracers [19-24].
Ideally, for radio-guided surgery, SB3 has to be radiolabeled with a gamma emitter that has a half-life enabling detection of radioactivity prior to surgery and during the full surgical procedure. For this purpose SB3 was therefore labeled with the clinically well-established γ-emitter indium-111 (111In; t1/2: 2.8 days). This [111In]SB3 can be used for SPECT/MRI, which offers the opportunity to combine sensitive functional imaging by SPECT with high-resolution anatomical/functional imaging by MRI. Compared to commonly used CT, MRI has a number of advantages such as improved soft tissue contrast and the added value of multiparametric imaging, which may lead to better tumor localization.
[111In]SB3 has poor in vivo stability, ultimately resulting in low tumor uptake [25]. An explanation for the poor in vivo stability is degradation of the peptide by naturally occurring enzymes in vivo, such as the neutral endopeptidase (NEP), which cleaves peptides at the amino side of hydrophobic residues [26, 27]. To increase the in vivo stability of radiopeptides multiple solutions are available, including structural modifications of a peptide or the novel approach of inhibition of enzymes responsible for enzymatic degradation. Since structural modifications are time-consuming, and may have a negative impact on the binding affinity or biodistribution profile of the peptide, the latter solution is very attractive. Co-administration of the NEP inhibitor phosphoramidon (PA) enhanced the in vivo stability and thereby the tumor targeting capacity of multiple radiotracers [5, 26, 28-30]. The aim of our study is to evaluate whether we can also improve tumor targeting of [111In]SB3 by co-administration of PA to potentially use the radiotracer for pre-operative SPECT/MRI and ultimately for intra-operative radio-guided tumor detection of GRPR-expressing tumors and/or metastases as well. For this we compared
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