Radiopeptides for Imaging and Therapy: A Radiant Future

Abstract

Radiopeptides are powerful tools for diagnostic imaging and radionuclide therapy of various diseases. Since the introduction of the first radiopeptide into the clinical setting to diagnose neuroendocrine tumors about 25 y ago, many advances have been made in the field. This short review highlights novel strategies to improve the application of radiopeptides for imaging and therapy.

Molecular imaging in neuroendocrine tumors: recent advances, controversies, unresolved issues, and roles in management

“…These include somatostatin-receptor scintigraphy (SRS) using ligands that are targeted to somatostatin-receptors (primarily sst2) overexpressed by NETs[7••, 28]. This method is now approved in many countries including the United States and utilizes primarily 111 In-DPTA-peptides, with SPECT/CT-imaging or using 68 Ga-DOTA-peptides with positron emission tomography (PET) combined with CT-imaging (PET/CT) or magnetic resonance imaging (PET/MRI)[7••, 8, 29•, 30–32]. Other molecular imaging approaches include the use of 18 F-FDG with PET/CT imaging which assesses glucose uptake by tumors[8, 29•, 31, 32, 33•]; 125 I-MIBG( 123 I-metaiodobenyzl-guanidine)-scintigraphy which utilitizes an analogue of guanidine, which is taken up by cells of sympathomedullary tissues and retained intracellularly by storage in catecholamine storage granules[8, 29•, 32]; and the use of 18 F-DOPA( 18 F-dihydroxyphenylalanine)PET or 11 C-5-hydroxy-L-tryptophan(5-HTP)( 11 C-5-HTP)- PET which takes advantage of the fact that NETs take up and decarboxylate amine precursors[8, 29•, 31, 32, 34].…”

“…PRRT will not be generally discussed in this review, however, it is receiving much attention as a therapeutic, targeted approach for patients with advanced NETs, and thus plays a role in the utilization of SRS, to assess whether this approach might be considered, by establishing the presence of somatostatin receptors on NET tissue [30, 32, 35, 41••, 42]. A recent prospective, randomized clinical trial (NETTER)[ 43•] using 177 Lu-DOTATATE in patients with unresectable advanced ileal NETs has been reported in preliminary communications to be effective with an acceptable safety profile.…”

“…In one study of 7 patients refractory to 90 Y/ 177 Lu-DOTATATE, all demonstrated enduring responses with favorable acute and midterm toxicity with 213 Bi-DOTATOC[104]. Other approaches being taken to increase the cytotoxicity of 90 Y-/ 177 Lu in PRRT include the use of combination therapies including using 90 Y-/ 177 Lu-DOTATATE together[105]; combined with PARP inhibitors to potentiate the accummulation of double-stranded DNA breaks and cytoxicity[106]; with peptide-degradation inhibitors such as phosphoramidon to increase tissue uptake[107, 108] or with chemotherapeutics to increase sensitivity such as temozolomide, or capecitabine and other anti-tumor agents such as everolimus[30, 109–112]. …”

Clinical History of the Theranostic Radionuclide Approach to Neuroendocrine Tumors and Other Types of Cancer: Historical Review Based on an Interview of Eric P. Krenning by Rachel Levine

“…For example, the implementation of radiolabeled compounds targeting prostate-specific membrane antigen (PSMA) for both diagnostic and therapeutic applications is considered to be a milestone in the management of patients with castration-resistant prostate cancer (46,47). The observation of frequent, persistent PSMA expression in such patients has provided the rationale for the recent introduction of PSMA radioligand therapy, with very promising initial results (46,65).…”

“…His interpretation is that the theranostic approach ("PRS positivity means PRRT feasibility"), as discussed here, is completely different from the general practice of chemotherapy. His hope is that future prospective phase 2 PRRT trials for other malignancies that express high levels of targetable peptide receptors, such as (castration-resistant) prostate cancer and breast cancer, may be sufficient for regulatory approval (46,47). To this end, approximately 15 different peptides (4,10,(48)(49)(50)(51)(52)(53)(54) were investigated in humans at Erasmus MC between 1987 and 2009, and various different peptides and developments exploring the potential utility of PRRT in oncology and other diseases have been reported since then (see the following text).…”