Design of New Imaging Agents Using Positron-Emitting Radionuclides as the Reporter
Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman in Molecular Imaging in Oncology, 2008
Somatostatin binds to the five subtypes of the somatostatin receptor. This receptor is upregulated on neuroendocrine tumors and this upregulation leads to a signal to background ratio that can be detected by external imaging. It also leads to tumor selectivity in therapeutic applications. The cyclic octapeptide octreotide is the analog most frequently labeled with metal chelates, such as 111In DTPA, 68Ga DOTA, and various 99mTc chelates for imaging and 111In DTPA and 90Y DOTA for therapy, all of which were selective for the somatostatin subtype receptor 2 (SSTR2) with IC50 values of less than 10 nM, whereas native somatostatin (SS-28) bound to all five subtypes with equally high affinity. Since these analogs have neurotransmitter properties, they are internalized which further increases the localization beneficial to imaging and therapy (59).
The pancreas, the neuroendocrine system, neoplasia, traditional open pancreatectomy
Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner in Endocrine Surgery, 2017
Discovery of membrane receptors to somatostatin and catecholamines permitted both functional identification and anatomic localization of neuroendocrine tumors with 111In-labeled somatostatin analogs (octreotide, pentetriotide, and lanreotide) and 131I-methyl-iodo-benzyl-guanidine, a norepinephrine analog (Table 41.5). Of the five somatostatin receptors (sstr), sstr-2 has the highest affinity to somatostatin or the long-acting analogs. Octreotide and lanreotide also exert effects on hormone secretion and antiproliferative activity by high-affinity binding to sstr-2 and, to a lesser degree, sstr-5. Hormonal hypersecretion is not a requisite for binding to somatostatin and its analogs, since nonfunctioning (silent) neuroendocrine tumors display similar receptor–ligand activity. Somatostatin receptor-based scintigraphy offers a high sensitivity and specificity (more than 90%), except for small tumors and insulinomas, where the diagnostic imaging accuracy drops to about 50%. Recent discovery of β cell receptors with high affinity to glucagon-like peptide (GLP-1) improved molecular imaging.
Regulation of the Pituitary Gland by Dopamine
Nira Ben-Jonathan in Dopamine, 2020
GHRH was originally isolated from a pancreatic tumor taken from a patient with acromegaly and somatotroph hyperplasia. GHRH is derived from a 108-amino acid prepro-hormone, which gives rise to GBRH(l–40) and [1–44], both of which are found in the human hypothalamus. GHRH binds to a GPCR-type receptor, activates adenylate cyclase and stimulates transcription of the GH gene and GH release. Somatostatin [also called somatotropin release inhibitory factor (SRIF)] is derived from a 116-amino acid prohormone that gives rise to two forms, somatoatatin-28 and -14, both of which are cyclic peptides due to an intramolecular disulfide bond. Somatostatin inhibits GH secretion directly from the somatotrophs and also reduces the impact of ghrelin by inhibiting its secretion from the stomach. There are five somatostatin receptor (SSTR) subtypes, with SSTR2 and 5 the most abundant in the pituitary.
Use of 68Ga DOTATATE, a new molecular imaging agent, for neuroendocrine tumors
Published in Baylor University Medical Center Proceedings, 2020
Raymond Andrew LeBlanc, Umesh D. Oza, Ryan Hayden, Hanna Fanous
Ki-67 is a histologic marker for cellular proliferation and correlates with the degree of differentiation of NET. There is an inverse relationship such that the lower the amount of cellular proliferation, the more somatostatin receptors are present. As such, the lower the Ki-67 level, the more activity is seen within the tumor on 68Ga DOTATATE scans (as 68Ga DOTATATE binds somatostatin receptors). A radiographic scoring system, called the Krenning Scoring System, can be used for 68Ga DOTATATE scans and is based on the amount of tumor uptake when compared to normal biodistribution. Patients with low Ki-67 and high 68Ga DOTATATE activity tumors can be considered for peptide receptor radionuclide therapy with therapeutic radiopharmaceuticals such as Lutetium-177.
Identification of somatostatin receptors using labeled PEGylated octreotide, as an active internalization
Published in Drug Development and Industrial Pharmacy, 2019
Somatostatin receptors (SSTRs) are memberships of the G-protein coupled receptor, GPCRs great family [1,2]. There are five subtypes of somatostatin receptors (SSTR1–5), while SSTR2 is classified into two subtypes, SSTR2A and SSTR2B [3,4]. The natural SST and its analogs bind with the receptor at a little nanomolar activity to yield distinct biological effects in all cells [2,5]. The SSTRs can be blocked with an antagonist to suppress the interaction with the receptor [6]. SSTRs are expressed in normal tissues such as monocytes, lymphocytes, duodenum, ovary, and myocardium. Moreover, SSTR2A is particularly expressed in many cells such as brain, pituitary, islet, stomach, and kidney [4,7]. Also, SSTRs are also expressed in numerous tumor cells such as small cell lung cancer [8–10], neuroendocrine cancer [11], breast cancer [12], and colorectal cancer [13]. Further, SSTR2 is expressed in numerous cancer such as glucagonoma 2 [14], metastatic lymph nodes [15], insulinoma [14,16–18], and pheochromocytoma [19]. Nevertheless, the majority of human tumors are mostly positive for SSTRs expression [20]. So, the identification of SSTR2 would be a favorable target for normal and diseased cells using branched labeled PEG as a very big molecule with nonspecific internalization [21]. These labeled branched PEGs would be useful also for the identification of cancer cells after attaching of the somatostatin analog octreotide, OCT. OCT was chosen as a ligand, as it is known for selectively bind to SSTR2.
Paraneoplastic Cushing syndrome, case-series and review of the literature
Published in Acta Clinica Belgica, 2018
Annelies Deldycke, Christel Haenebalcke, Youri Taes
In 2009, a typical carcinoid tumor with two lymph node metastases in the left lung was detected in a 65-year-old male patient, known with diabetes mellitus type 2 and arterial hypertension. He underwent a complete left pneumonectomy. In November 2014, bone and liver metastases as well as a local relapse in the mediastinum were found. An octreotide scan showed expression of the somatostatin receptors in the tumoral lesions, after which, treatment with a somatostatin analog was started. During follow-up, about one year later, overt hyperglycemia developed, requiring insulin treatment. Furthermore, some clinical characteristics were striking, such as a buffalo neck and thin skin witch ecchymoses. Hypercortisolemia was suspected. Diagnostic work up (illustrated in Table 2) demonstrated an ACTH-dependent Cushing syndrome. A magnetic resonance imaging (MRI) of the brain was performed but showed no pituitary lesions. Ectopic ACTH secretion was highly suspected and the dose of the somatostatin analog was increased. Clinical situation didn’t improve and serum cortisol and 24 h urinary-free cortisoluria increased. Kétoconazole was associated, without clinical improvement. Eventually, a bilateral adrenalectomy had to be performed. Despite the development of the Cushing syndrome, no tumor progression was found.
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