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Nuclear Medicine Unit, Department of Medical‐Surgical Sciences and of Translational Medicine, Faculty of Medicine and Psychology, “Sapienza” University of Rome, Rome, Italy


background blood pool activity after few minutes from injection. They can be synthetic or of natural human recombinant origin and do not usually elicit allergic reactions.

Somatostatin (SST) is a peptide with a broad distribution in the nervous system and acts as a neurotransmitter in several organs, having a wide range of mainly inhibiting effects, such as the suppression of growth hormone release, as well as the inhibition of pancreatic and gastrointestinal hormone release [1, 2]. five SST receptor (SSTR) subtypes have been cloned, of which SSTR1 and SSTR4 are grouped into one family and SSTR2, SSTR3, and SSTR5 into another. They all are g‐protein‐

coupled receptors located at the cell membrane [3], which recognize the ligand and generate a transmembrane signal. The resulting hormone–receptor complexes have the ability to be internalized. once internalized, these vesicles fuse with lysosomes, resulting in hormone degradation or receptor recycling [4]. SSTR2 appears to be the most frequently represented receptor subtype over the surface of neuroendocrine tumor (NET) cells [5] and activated lymphocytes providing the molecular basis for many clinical applications of radiolabeled SST analogues [6]. Toward the end of the 1980s, the in vivo demonstration of SSTRs on the surface of some tumors raised interest in receptor imaging [7], and indeed, the peptide receptor overexpression on tumors cells, as compared to normal tissues [8, 9], constituted the basis for molecular imaging of these tumors.

both natural SST‐14 and SST‐28 bind with high affinity to all five SSTRs but have a short plasma half‐life (~3 min) owing to rapid enzymatic degradation by endogenous peptidases. first attempts to label recombinant SST‐28 were made by Signore and coworkers at the “Sapienza” University of Rome, italy, in 1982.

The SST was labeled with 123i and used for imaging pituitary tumors.

Unfortunately, the plasma half‐life of this hormone was extremely rapid, thus not allowing good imaging with the available technology. in an early study by Amartey et al. [10], SST was labeled with 99mTc. As could be expected in view of its short half‐life, no specific accumulation in receptor‐rich tissue was observed. in the following years, the availability of SSTR analogues with a longer half‐life (of 1.5–2 h) and preserved receptor binding has allowed significant improvements for diagnosis and therapy of NET. furthermore, SST analogues have no major side effects, and their use is very safe, particularly when used as radiopharmaceuticals [11].

molecular imaging by radiolabeled SST analogue highlights the presence of path-ological tissues overexpressing SSTR. it can be used to characterize lesions with respect to the expression of SSTR, to contribute to differential diagnosis, for staging diseases by detecting or excluding sites of metastases, and for grading the disease since in NET the loss of the expression of SSTR is a sign of dedifferentiation and has a poor prognostic value.

Somatostatin receptor scintigraphy (SRS), however, is not disease specific but receptor specific, and to be able to interpret the results of the scan, one needs to understand the underlying tumor biology. A negative scan may indicate absence of tumor, tumor regression, or tumor dedifferentiation. correlation with anatomical imaging is always mandatory.


The application of 111in‐labeled octreotide analogue to target SSTRs on tumor cells still represents a paradigm in the field of peptide radiopharmaceuticals. The SST analogue 111in‐labeled octreotide (octreoScan) was officially introduced in 1994, and its use to visualize various SSTR‐positive tumors and tissues is widely accepted. many tumors (most of them neuroendocrine related) may express a combination of the five receptor subtypes (SSTR1–SSTR5) in different percentages [12, 13].

Since that time, a very large “panel” of tumors and diseases were studied by octreoScan scintigraphy, and extensive clinical studies have been performed mainly in NET [14–20] but also in other tumors like brain tumors [21], melanomas [22], and lung [23] and breast [24] cancer. in order to overcome the limitations of the use of octreoScan like the high cost of 111in (a cyclotron‐produced radionuclide) and the nonoptimal physical features of this radioisotope, many SST analogues have been labeled with 99mTc. depreotide, a synthetically produced ten‐amino‐acid peptide with affinity for SSTR2, SSTR3, and SSTR5, has been labeled with 99mTc [25] and suc-cessfully used to characterize malignancy in solitary pulmonary nodules [26].

Another interesting peptide is vapreotide, which binds SSTR2 and SSTR5 with high affinity and moderately to SSTR3 and SSTR4 and has been used in animals [27].

Another promising radiopharmaceutical, the 99mTc‐hYNic‐tyr(3)‐octreotide, has been labeled and successfully used in humans [28–31].

A further evolution in the field of SST analogues is represented by the development of macrocyclic chelators that exhibit the property to bind also beta particle emitters like 90Y and 177lu. These chelators include doTA, doTAoc, doTAToc, doTAVAP, doTATATE, and lanreotide doTAlAN. These radiolabeled compounds including these chelators seem to show favorable binding and biodistribution characteristics with high uptake and retention in target organs, thus being promising candidates for peptide receptor radionuclide therapy. it is well known that at least one of the first generation of 90Y‐labeled octreotide analogues, 90Y‐doTAToc, has real therapeutic activity in the treatment of NET, which have proved resistant to other forms of treatment [32, 33].


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Somatostatin Analogues: From Research to Clinical Practice, First Edition. Edited by Alicja Hubalewska-Dydejczyk, Alberto Signore, Marion de Jong, Rudi A. Dierckx, John Buscombe, and Christophe Van de Wiele.

© 2015 John Wiley & Sons, Inc. Published 2015 by John Wiley & Sons, Inc.


BCA bifunctional metal chelating agent

COST European Cooperation in Science and Technology

CT computed tomography

DFO desferrioxamine

DOTA 1,4,7,10‐tetraazacyclododecane‐1,4,710‐tetraacetic acid DTPA diethylenetriaminepentaacetic acid

EDDA ethylenediamine‐N, N′‐diacetic acid

GEP‐NET gastroenteropancreatic neuroendocrine tumor HYNIC hydrazinonicotinamide

IAEA International Atomic Energy Agency MEAP medium‐energy all‐purpose collimators MEN‐1 multiple endocrine neoplasia type 1 MIBG metaiodobenzylguanidine

MRI magnetic resonance imaging NET neuroendocrine tumor

NHS‐HYNIC N‐hydroxysuccinimidyl hydrazinonicotinamide

somAtostAtin receptor