*4.1.1 Radionuclide therapy using somatostatin analogues*

PRRT and radiolabeled somatostatin (SST) peptide analogues are highly effective treatment agents. Somatostatin is in the form of dominant but functionally less active 14 amino acids called SST-14 and SST-28 in the form of a larger and stronger 28 amino acids [73]. According to the structure-activity researches of SST-14, although the amino acid residues of Phe, Trp, Lys, and Thr which contain a β-turn are important for bioactivity, different amino acids may be replaced by the Phe and Thr amino acids for this bioactivity, whereas Trp and Lys residues are definitely required. Octreotide, lanreotide, vapreotide, and pasireotide, which are the 4SS analogue synthetic peptides, are currently used actively in routine clinical applications. The octreotide compound, which is the synthetic peptide compared to the natural SST, was found to be 19 times more effective in inhibition of growth hormone secretion [74]. The presence of the D-Phe at the N-terminal end and the L-Thr at the C-terminal end and the replacement of the L-Trp at position 8 with D-Trp ensure that the peptide is resistant to degradation [75]. The somatostatin receptor family contains five receptor subtypes, sst1–sst5. Most of the neuroendocrine tumors, especially subtype 2 (sst2), have a strong overexpression of sst. The clinical use of radiolabeled sst-targeting analogue [111In-DTPA0 ]octreotide initiated the development of numerous somatostatin analogues. This analogue is used as a theranostic agent in positive metastatic tumors. Tumor regression and survival improvement can be provided with [90Y-DOTA0 ,Tyr3 ]octreotide and [177Lu-DOTA0 ,Tyr3 ]octreotate. Several phase-1 and phase-2 PRRT trials were carried out using [90Y-DOTA0 -Tyr3 ]octreotide. Tumor regression responses in the clinical studies with these agents in patients who suffered from GEP-NETs ranged from 9 to 33% [70]. As a result of the administration of the radiolabeled antagonist 125I-JR11 and agonist 125I-Tyr3 -octreotide in different tumors, it was found that the antagonist binds to the SSTR2 region at a rate of 3.8–21.8-fold higher [76]. This significantly increased binding not only provides a more accurate localization in tumor and metastasis but also enables therapeutic interventions with radiolabeled SSTR antagonists to be more effective. Despite the low SSTR2 concentrations, tumors other than GEP-NETs and lung NETs have been targeted with SSTR2 antagonists; tumors of these types are breast cancer, medullary thyroid cancer, non-Hodgkin lymphomas, renal cell cancer, and small-cell lung cancer [76, 77].

#### *4.1.2 Radionuclide therapy using PSMA analogues*

PSMA has become an interesting target for the diagnosis and therapy of peptide receptors for small molecule ligands [78]. Since PSMA is often overexpressed in prostate cancer (PCa) cases, many different PSMA ligands are aimed to be targeted by the same biological mechanism to diagnose and treat metastatic castration-resistant prostate cancer (mCRPC). Many studies proved the superiority of 68Ga-PSMA PET/CT (positron emission tomography/computed tomography) as compared to CT, MRI, or bone scan for determination of metastases for first staging at initial diagnosis [79, 80]. Imaging with PSMA in nuclear medicine substantially affected the detection and treatment of patients with prostate cancer. PSMA has been known to be promising and frequently preferred in advanced clinical studies because of providing preliminary information for different types of clinical conditions and detecting lesions with low PSA levels [81]. PET/CT data obtained using PSMA provides a noninvasive evaluation of PSMA expression and is used for restaging prostate cancer after radical prostatectomy when PSA level is low [82]. Also, it can be applied in endoradiotherapy because of the intracellular internalization feature of PSMA. A small molecule inhibitor of PSMA ((S)-2-(3-((S)-1-carboxy-5-(3-(4-[124I]iodophenyl) ureido) pentyl)ureido)pentanedioicacid; MIP-1095) has been administrated to evaluate potential therapeutic use of 131I-MIP-1095 in men with mCRPC [83]. Due to their molecular and specificity similarity, 68Ga-PSMA-11, 68Ga-PSMA-617, and 68Ga-PSMA-I&T are abbreviated as 68Ga-PSMA. 68Ga-PSMA-11 biodistribution was known to correspond well to cellular detection of PSMA expression. 68Ga-PSMA-617 and 68Ga-PSMA-I&T peptidic ligands demonstrated similar distribution and imaging properties [79].
