**5. Peptide receptor radionuclide therapy (PRRT)**

Several radionuclides have been used for peptide therapy in neuroendocrine tumor (NET) patients. The expression of peptide receptors on various tumor cells, including NETs, was significantly higher than normal tissues or cells [25]. Over the last decade, such receptors have become recognized targets for molecular imaging and therapy because they are expressed on the cell surface. Upon binding a ligand, the receptor-ligand complex is internalized. Radiolabeled peptide ligands are known to be used for imaging and somatostatin receptor therapy (SSTR) [25].

Peptide receptor radionuclide therapy (PRRT) has been known to be an effective systemic treatment of patients with advanced, metastatic, or inoperable, slowly progressing NETs with high somatostatin receptor expression. The principles behind PRRT efficacy are the somatostatin receptor ligand that binds the specific receptor (SSTR1–5). Particularly, SSTR2 overexpressed on the surface of neuroendocrine tumor cells. The high energy of β-particle (90Y or 177Lu) labeled to a somatostatin receptor (SSTR) ligand caused cell death through direct or indirect DNA damage of target cells (self-dose) or neighboring cells (crossfire effect) [42]. The binding of the radiopharmaceutical to the targeted cells will be indispensable when using Auger emitters. Beta-particles become more effective in damaging and killing target cells that radiopharmaceutical is bound to and several cells around the target. It is the so-called "crossfire" effect. Lower tissue penetration of 177Lu favors the use in small-sized tumors, whereas, in larger tumors, 90Y might be a better choice [25]. 117Lu or 90Y labeled DOTATATE (DOTA, Tyr(3)-octreotate) was the most widely used peptide. It is a higher SSTR2 affinity compared to DOTATOC (DOTA, D-Phe1, Tyr (3)-octreotide) and DOTANOC (DOTA, 1-Nal(3)-octreotide) [43].

Furthermore, targeted peptide receptor alpha therapy with 213Bi/225Ac has been clinically tested to treat brain tumors, neuroendocrine tumors, and prostate cancer. 213Bi and 225Ac-DOTA chelated peptides developed for peptide receptor radiotherapies, such as DOTA-Substance P targeting the neurokinin-1 receptor and the widely used somatostatin-analogs (e.g., DO-TATOC, DOTATATE). The complexation efficiency, in vitro and in vivo stability of the radiopeptides is high [1, 44]. However, these promising results still need to be confirmed in further studies with therapeutic activities 213Bi and 225Ac.
