Abstract
BackgroundSomatostatin receptor targeting radiopeptides are successfully being used to image, stage, and monitor patients with neuroendocrine tumours. They are exclusively agonists that internalise upon binding to the relevant receptor. According to recent reports, antagonists may be preferable to agonists. To date, 99mTc-labelled somatostatin receptor antagonists have attracted little attention. Here, we report on a new somatostatin receptor subtype 2 (sst2) antagonist, SS-01 (p-Cl-Phe-cyclo(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)D-Tyr-NH2), with the aim of developing 99mTc-labelled ligands for SPECT/CT imaging. SS-01 was prepared using Fmoc solid-phase synthesis and subsequently coupled to the chelators 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 6-carboxy-1,4,8,11-tetraazaundecane (N4), and 6-hydrazinonicotinic acid (HYNIC) to form the corresponding peptide-chelator conjugates SS-03, SS-04, and SS-05, respectively. SS-04 and SS-05 were radiolabelled with 99mTc and SS-03 with 177Lu. Binding affinity and antagonistic properties were determined using autoradiography and immunofluorescence microscopy. Biodistribution and small animal SPECT/CT studies were performed on mice bearing HEK293-rsst2 xenografts.ResultsThe conjugates showed low nanomolar sst2 affinity and antagonistic properties. 177Lu-DOTA-SS-01 (177Lu-SS-03) and 99mTc-N4-SS-01 (99mTc-SS-04) demonstrated high cell binding and low internalisation, whereas 99mTc-HYNIC/edda-SS-01 (99mTc-SS-05) showed practically no cellular uptake in vitro. The 99mTc-SS-04 demonstrated impressive tumour uptake at early time points, with 47% injected activity per gram tumour (%IA/g) at 1 h post-injection. The tumour uptake persisted after 4 h and was 32.5 %IA/g at 24 h. The uptake in all other organs decreased much more rapidly leading to high tumour-to-normal organ ratios, which was reflected in high-contrast SPECT/CT images.ConclusionsThese data indicate a very promising 99mTc-labelled sst2-targeting antagonist. The results demonstrate high sensitivity of the 99mTc-labelling strategy, which was shown to strongly influence the receptor affinity, contrary to corresponding agonists. 99mTc-SS-04 exhibits excellent pharmacokinetics and imaging properties and appears to be a suitable candidate for SPECT/CT clinical translation.
Highlights
Somatostatin receptor targeting radiopeptides are successfully being used to image, stage, and monitor patients with neuroendocrine tumours
Somatostatin receptors are important biomarkers for imaging and targeted radionuclide therapy of human cancers. They belong to the large family of G-protein coupled receptors, which currently account for 30–40% of marketed drugs [1] and are overexpressed in neuroendocrine tumours in particular and in non-neuroendocrine tumours [2]
We report here the synthesis of a new somatostatin-based antagonist, 4-Cl-Phe-cyclo(D-CysTyr-D-Trp-Lys-Thr-Cys)D-Tyr-NH2 (SS-01), which was designed for labelling with 99mTc using two different strategies, namely N4: 6-carboxy-1,4,8,11-tetraazaundecane (SS-04) and hydrazinonicotinic acid (HYNIC): 6-hydrazinopyridine-3-carboxylic acid (SS-05), as metal-binding domains
Summary
Somatostatin receptor targeting radiopeptides are successfully being used to image, stage, and monitor patients with neuroendocrine tumours They are exclusively agonists that internalise upon binding to the relevant receptor. Ginj et al have shown that in both in vitro and in vivo animal models, somatostatin-based radioantagonists may be superior to radioagonists [5] These findings have recently been duplicated with antagonists conjugated with DOTA and NODAGA and labelled with the positron-emitting radiometals 68Ga and 64Cu and other 3+ (radio)metals [6,7,8] and further supported by first-in-human imaging and therapy studies [9,10,11,12]. Preclinical [13,14,15,16] and clinical [17] studies of bombesin-based radioantagonists showed that using antagonists may be advantageous over agonists for targeted imaging and therapy of GRP receptor-express ing tumours
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
