Neuroendocrine tumor targeting: Study of novel gallium‐labeled somatostatin radiopeptides in a rat pancreatic tumor model

Abstract

Somatostatin analogs labeled with radionuclides are of considerable interest in the diagnosis and therapy of SSTRexpressing tumors, such as gastroenteropancreatic, small cell lung, breast and frequently nervous system tumors. In view of the favorable physical characteristics of the Ga isotopes 67 Ga and 68 Ga, enabling conventional tumor scintigraphy, PET and possibly internal radiotherapy, we focused on the development of a Ga-labeled somatostatin analog suit- SSTRs are overexpressed by a variety of neuroendocrine tumors and frequently by tumors of the nervous system, 1-4 making somatostatin analogs, such as OC, 5 attractive candidates for tumor targeting. 111 In-labeled DTPA-OC (OctreoScan) was the first radiopeptide routinely used in the clinic for imaging SSTR-positive tumors by scintigraphy. 6 -10 A new generation of somatostatin analogs, incorporating the macrocyclic chelator DOTA instead of DTPA, have been developed, which ensure better stability of the radiometal-peptide complex. After labeling with 90 Y (␤ --emitter 2.28 MeV, t 1 ⁄2 64.1 hr) or 111 In (␥-emitter, Auger-and conversionelectron emitter, 0.5-245 keV, t 1 ⁄2 67.9 hr), they showed improved biodistribution and tumor uptake in animal models [11][12][13] and their clinical utility as diagnostic and therapeutic tools was confirmed in patients. 14 -18 These findings prompted us and others to develop somatostatin analogs suitable for PET, which offers higher sensitivity and resolution than SPECT, making it possible to visualize very small metastatic lesions, including tumor deposits in regional draining lymph nodes. Several strategies have been studied to develop a somatostatin analog-based PET tracer using different positronemitting radionuclides. Wester et al. 19 successfully labeled OC with 18 F, but despite specific accumulation in the tumor, this radioligand was of limited clinical application, owing to fast tumor washout, high liver uptake and, hence, insufficient visualization of abdominal tumors. Various 64 Cu-labeled somatostatin analogs were synthesized which showed favorable biodistribution in animal models 20,21 and good performance for PET imaging in patients; 22 however, the use of 64 Cu relies on the availability of a cyclotron.Another interesting positron emitter is 68 Ga (t 1 ⁄2 68 min, ␤ ϩ 88%), which is produced by a 68 Ge/ 68 Ga generator available at most PET centers and is not dependent on a cyclotron. Gallium as radiometal is of even broader interest in nuclear medicine because it is also available as 67 Ga (t 1 ⁄2 78 hr), which is not only a ␥-emitter useful for tumor diagnosis (␥-camera scintigraphy, SPECT) but also an emitter of Auger (0.1-8 keV) and conversion (80 -90 keV) electrons, which makes it attractive for internal radiotherapy. 23 The radiotoxicity of 67 Ga has been demonstrated in vitro in a lymphoma cell line 24 and myeloid leukemic blasts. 25 The use of a low-energy emitter might increase the therapeutic index because most of the electrons deposit their energy within the target, i.e., the tumor, thereby min...

First 18F-Labeled Tracer Suitable for Routine Clinical Imaging of sst Receptor-Expressing Tumors Using Positron Emission Tomography

“…The fact that for all of the fluorinated TOCA derivatives Ͼ96% of the initial cellular activity was externalized within 60 min under conditions inhibiting recycling (5 M TOC) indicates a negligible extent of intracellular ligand residualization. This represents one major disadvantage of radiohalogenated over radiometallated octreotide analogs, of which the charged radiometal-chelate-containing fragments remain trapped in the lysosomal compartments after degradation (7,47,48). The high extent of apparent intracellular retention of [ F-labeled TOCA derivatives in this study between 10 and 60 min p.i.…”

“…Due to the ease of radiometallation, a variety of chelatorcoupled octreotide derivatives have been labeled with positronemitting radiometals such as 86 Y (1-3), 64 Cu (4 -6), and 66/68 Ga (7)(8)(9)(10). Initial patient PET studies using 64 Cu-triethylenetetraamine-octreotide as well as [ 66 (3).…”

Imaging of gastroenteropancreatic neuroendocrine tumors

“…In contrast, gamma-based SRS has reported sensitivity and specificity for non-insulinoma pancreatic NETs of approximately 80%-90% [86,87] , and is indicated for use in pre-therapy localization and staging, especially when demonstration of extra-hepatic metastatic lesions is required. Several reports have established the promising utility of PET-based SRS for imaging non-insulinoma pancreatic NETs [88][89][90] . The use of PET-based SRS is expected to have improved resolutive capabilities as compared with conventional gamma-based SRS, in keeping with findings from gastrointestinal carcinoid imaging, but further validation is needed.…”

Functional imaging of neuroendocrine tumors with combined PET/CT using 68Ga‐DOTATATE (DOTA‐DPhe1,Tyr3‐octreotate) and 18F‐FDG

“…68 Ga-DOTATATE has high affinity for SSR-2, is rapidly excreted from nontarget sites, offers good target to nontarget imaging properties, and hence is an ideal potential candidate tracer for imaging NETs. [2][3][4][5] Recent studies have indicated that 68 Ga-labeled DOTA peptide DOTATOC has potential to improve imaging for NET over conventional 111 indium pentetreotide. [5][6][7] NETs, however, typically have a wide range of cellular differentiation.…”