Novel 99mTc-labeled Somatostatin Antaginosts in the Diagnostic Algotithm of Neuroendocrine Neoplasms

Neuroendocrine neoplasms (NEN) are a heterogeneous group of malignancies that arise from various endocrine glands, endocrine cells within non-endocrine tissue and diffuse endocrine cells of the gastrointestinal, respiratory and genitourinary tract. Detection of NEN and monitoring of their response to therapy is challenging due to their varied location (often-unknown primary focus) and cellular heterogeneity. NEN exhibit a wide range of histological appearances and biological behaviors, and may all potentially behave in an aggressive manner, irrespective of the initial diagnosis. Consequently, the prediction of clinical outcomes in an individual patient is often difficult and inaccurate. According to some national registries, the incidence of NEN increased more than 6-fold and the prevalence more than 8-fold between 1973 and 2012, making NEN the second most prevalent diagnosis in gastrointestinal malignancies, thus representing a growing challenge. The rise in the incidence can be partly attributed to increased awareness of the disease and better detection methods. Diagnostic imaging is an integral part of the management of patients with NEN by localising the primary or recurrence site, determining the extent of the disease and evaluating response to therapy. Nuclear medicine with single-photon emission tomography (SPECT) and positron emission tomography (PET) is a branch of molecular imaging: in contrast to anatomical imaging, it depicts functional changes and biological characteristics of target tissues, providing a unique insight into the biology of malignant disease, and has established itself as an excellent tool in personalized medicine. The characteristic feature of NEN is an overexpression of somatostatin receptors (SSTR) on cell membranes. Molecular imaging techniques utilise the ability of SST analogues labelled with radioactive (single-photon or positron emitting) nuclides to bind to the SSTR. A combination of molecular and anatomical imaging (hybrid imaging, SPECT/CT and PET/CT) is currently the most sensitive approach to visualisation of SSTR-positive tumours. In NEN patients the prognosis depends on the grade and stage of the tumour. However, SSTR expression determines not only efficacy of staging using molecular imaging methods, but also efficacy of antiproliferative therapy with SST analogues both not radiolabelled ("cold") and labelled with a therapeutic radionuclide thus enabling Peptide Receptor Radionuclide Therapy (PRRT) as the main approach to personalised NEN patients' management. Traditionally, radiolabelled SST analogues were constructed aiming at their agonistic behaviour, based on their internalisation after SSTR activation and consequent retention within the tumour cells, believed to be crucial for efficient molecular imaging and therapy. Recently, it has been shown that novel molecular probes, SSTR antagonists, recognise more binding sites and hence improve diagnostic efficacy, especially when the density of SSTR is low. Accumulating preclinical and clinical data using both SPECT and PET tracers shows that high-affinity SSTR antagonists can provide better SSTR visualisation than agonists. Preclinical data and subsequent clinical evaluation demonstrated higher tumour uptake of an In-111-labelled antagonist [111In]In-DOTA-sst2-ANT ([111In]In-DOTA-BASS) compared to the agonist [111In]In-DTPA0-octreotide or [111In]In -DTPA0-octreotate, as well as superior tumour-to-background ratios. One of the first reports describing the SSTR2 antagonist LM3 indicates the high potential of gallium-68 (Ga-68) and copper-64 (Cu-64) radiolabelled LM3 in PET/CT. The authors demonstrated strong dependence of the affinity and pharmacokinetics of the SST-based radiolabelled antagonists on the chelator and radiometal, also confirmed using another SSTR antagonist, namely JR11. The Superiority of the SSTR antagonist was demonstrated in the Phase I/II clinical study using a positron emitter, [68Ga]Ga-NODAGA-JR11 and in a pilot study conducted with beta-emitting, therapeutic radionuclide (lutetium-177, Lu-177) labelled SSTR antagonist [177Lu]Lu-DOTA-JR11. As a result, research in the field is currently strongly focused on SSTR antagonists. Ga-68-labelled SST analogues have already established PET as a unique tool for personalising treatment of NEN. Nevertheless, single-photon emitting radiopharmaceuticals still represent the cornerstone of molecular imaging, particularly those based on Technetium-99m (Tc-99m). Its physical properties (half-life of 6 hours, optimal energy of 140 keV for imaging and lowest radiation exposure), widest on-site availability and cost-effectiveness are of major importance for routine clinical applications. Medical diagnostic imaging techniques using Tc-99m account for approximately 80% of all nuclear medicine procedures, representing 30-40 million examinations worldwide every year; even in developed countries, the number of gamma cameras in use exceeds by far the number of PET systems. Considering the above-mentioned characteristics Tc-99m is perfect for research with new radiotracers and is still recognised as the workhorse of diagnostic nuclear medicine. Quantifiable uptake of the radiopharmaceutical in target tissue using standardised methods and metrics such as standardised uptake value (SUV) is currently a unique feature of PET allowing highly personalized approaches to patient management and is part of clinical routine. It was shown also in NEN that the quantitative approach is able to adequately predict and evaluate the response to various treatments available, including "cold" and radiolabelled somatostatin analogues (PRRT). However, single-photon quantitative imaging has developed significantly and is also entering clinical routine. Identical quantitative metrics are becoming available with the use of SPECT/CT systems (SPECT SUV) with comparable accuracy and clinical applicability. The development of a quantitative SPECT imaging approach in NEN, in combination with improved, widely available radiopharmaceuticals, would therefore represent a highly significant improvement in management, tailored to the needs of each individual patient.