Besides radiolabeled somatostatin analogs, the use of radiolabeled somatostatin antagonists represents a highly promising strategy for both SPECT and PET imaging [1, 32]. Preliminary experiences showed that the radiolabeled antagonist ¹¹¹In-DOTA-BASS may be preferable to agonists because of a higher and longer retention in tumors and better imaging results [33]; so, a greater benefit on radioreceptor therapy is expected [34]. Among new SPECT tracers, specific radioligands for glucagon-like peptide-1 (GLP-1) receptors have been recently developed and evaluated in animal models and in humans [35, 36]. GLP-1 is an intestinal hormone that stimulates insulin secretion through receptors expressed in islet cells. GLP-1 receptors are greatly expressed in insulinomas, and recent studies demonstrated that an ¹¹¹In-labeled GLP-1 analog (¹¹¹In-exendin-4) can detect occult insulinomas, which were not localized by other imaging modalities [35, 36]. ⁶⁸Ga-exendin-4 has been recently applied for PET/CT imaging [37].

Many different radiopharmaceuticals are available for imaging of pancreatic neuroendocrine neoplasms (as other GEP-NENs) based on their physiopathology, which is characterized by different metabolic pathways and different receptor expression.

SRS with ¹¹¹In-octreotide still today is a widely used functional imaging modality for GEP tumors, due to its worldwide availability together with good diagnostic sensitivity, which is ≥80 % in various studies with the only exception of insulinomas due to the low density of sstr2 in these tumors and its ability in changing patient management in approximately 30 % of cases [2]. ^99mTc-labeled somatostatin analogs (^99mTc-HYNIC-TOC and ^99mTc-HYNIC-TATE) have been proposed as promising candidates for an alternative to ¹¹¹In-DTPA-octreotide for SRS [6]. The main limitations of SRS are its relatively low spatial resolution (about 1 cm) and the lack of a precise localization of the neoplastic lesions when a SPECT/CT device is not available.

The initial clinical applications of ⁶⁸Ga-DOTA-peptides have shown several advantages over ¹¹¹In-DTPA-octreotide [38–40]: higher diagnostic sensitivity (>90 %), especially in detecting small primary tumors and metastatic lesions, due to the higher spatial resolution (4–6 mm) and higher count rate sensitivity of PET devices; quantification of the uptake by the standardized uptake value (SUV); lower radiation exposure; single-day procedure (versus 2–3 days for SRS if a hybrid machine is not available), with better patient comfort and faster reporting; and lower costs [40, 41]. Also the superiority of ⁶⁸Ga-DOTATATE over ^99mTc-HYNIC-TOC has been recently demonstrated [42]. ⁶⁸Ga-DOTA-peptide PET/CT has shown to be the most sensitive procedure for the detection of unknown primary NENs; among the detected primary tumors, a significant number is located in the pancreas (46 % in the experience by Prasad et al.) [43]. In the presence of a pancreatic mass, a positive scan suggests the presence of a well-differentiated NEN (Fig. 3.2). On the contrary, a negative scan suggests an adenocarcinoma or a poorly differentiated neuroendocrine neoplasm; in these cases, an intense ¹⁸F-FDG uptake is frequently observed. In any case, preoperative cytologic/histologic confirmation is needed. In addition, ⁶⁸Ga-DOTA-peptide PET/CT can affect either stage or therapy in approximately 50 % of patients with NEN [44] and plays a distinctive role in guiding the selection of therapy with cold or radiolabeled somatostatin analogs.

¹⁸F-DOPA is particularly suited to visualize carcinoid tumors with elevated serotonin levels [2, 45] and is the imaging technique of choice in children with congenital hyperinsulinism to distinguish focal from diffuse forms [46, 47]. On the contrary, controversial results have been reported in localizing neuroendocrine pancreatic tumors in adults [48–50]. Due to the physiologic pancreatic uptake, false-negative findings with ¹⁸F-DOPA PET have been reported both in functioning and nonfunctioning neuroendocrine pancreatic tumors in adults as well as in patients with pancreatic islet cell tumors who had been pretreated with carbidopa, suggesting that carbidopa premedication should be avoided when such tumors are suspected [48]. Recent observations seem to reassess the value of ¹⁸F-DOPA PET/CT after carbidopa premedication in insulin-secreting tumors in adults [51]. Abnormal ¹⁸F-DOPA uptake in a pancreatic tumor not of neuroendocrine origin (i.e., solid pseudopapillary tumor) has been recently reported, doubting the specificity of this tracer [52].

The uptake of ¹¹C-5-HTP in NENs is based on the same mechanism as for ¹⁸F-DOPA; however, few data are available about the use of ¹¹C-5-HTP due to its complex production and limited availability. ¹¹C-5-HTP can be used both in patients with increased serotonin synthesis, i.e., with carcinoid tumors, and patients without elevation of urinary 5-HIAA, i.e., with neuroendocrine pancreatic neoplasms [53]. In comparative studies, ¹¹C-5-HTP PET showed the highest sensitivity (96 %) for the detection of pancreatic NENs as compared with CT, SRS, and ¹⁸F-DOPA PET [28]. False-negative results may occur in poorly differentiated neoplasms [48, 53].

¹⁸F-FDG frequently fails to visualize tumors with a low proliferation rate, i.e., well-differentiated NENs (G1), whereas it is recommended for identification and assessment of poorly differentiated (G3) neuroendocrine carcinomas [54, 55]. In patients with NEN, the so-called “flip flop” pattern of uptake may be observed, i.e., ⁶⁸Ga-peptide positive and ¹⁸F-FDG negative in well-differentiated tumors and vice versa in poorly differentiated carcinomas [2] (Fig. 3.3). However, ¹⁸F-FDG positivity has been reported also in a substantial percentage of G1 and G2 NENs, where it offers important prognostic information, predicting early progression and influencing the therapeutic management [56]. Recently, a metabolic grading system based on the tumor-to-liver ratio of ¹⁸F-FDG uptake has been assessed in patients with inoperable multifocal gastroenteropancreatic NEN [57].

Considering the wide availability of radiopharmaceuticals that target endocrine tumor cells, how to choose the most appropriate one in the clinical practice for imaging endocrine pancreatic neoplasms? The choice depends on several factors including:

Therefore, the preferential use of a given tracer should be defined in the specific clinical context (Table 3.1). When the diagnostic information is needed, i.e., for lesion identification and localization (including unknown primary) and disease staging and restaging after therapy, the choice should be primarily guided by tumor differentiation and grading. In well-differentiated pancreatic neuroendocrine tumors (G1 and low G2), functional imaging with radiolabeled peptides should be performed. In this context, ⁶⁸Ga-DOTA-peptide PET/CT is currently regarded as the nuclear medicine technique of choice; where available, it has replaced OctreoScan^®, which maintains a role just for evaluating the receptor status prior to therapy with cold or radiolabeled somatostatin analogs (⁹⁰Y- or ¹⁷⁷Lu-DOTA-peptides) [58]. In fact, PET/CT with ⁶⁸Ga-DOTA-peptides provides the same information of SRS with a higher diagnostic accuracy and a lower patient discomfort.