*4.1.3.1 GRP receptor-targeting peptides*

Overexpression of gastrin-releasing peptide receptors (GRPR) is seen in many human tumors, including prostate and breast tumors. Bombesin (BN), a 14-amino acid peptide with high affinity to the GRP receptor, is used for GRP receptortargeted tumor imaging and treatment. 111In- and 99Tcm-labeled BN analogues have been improved for SPECT imaging of GRP receptors. After a while, a novel DTPA-bound BN analogue, [111In-DTPA-ACMpip5, Tha6, βAla11, Tha13, Nle14] BN (5–14) (Cmp 3), was synthesized. Replacement of the DTPA chelator in the 111In-Cmp3 analogue with a DOTA makes the compound suitable for therapeutic use and diagnostic PET imaging. Another promising peptide-conjugated DOTA is 177Lu-AMBA (DOTA-BN (7–14)), which exhibits good tumor-background ratios. The 177Lu-AMBA is excreted through the kidneys, but kidney excretion cannot be reduced by co-lysine injection because there is not any lysine in the peptide structure. Nowadays, it is the first choice in the targeting of 68Ga GRP receptors as a positron emitter radionuclide which provides shorter half-life and in-house radiolabeling procedures as well as more accurate high-resolution PET images. Recently,

**13**

noma localization [88].

*Synthesis and Applications of Synthetic Peptides DOI: http://dx.doi.org/10.5772/intechopen.85486*

*4.1.3.2 NT receptor-targeting peptides*

*4.1.3.3 CCK2 receptor-targeting peptides*

*4.1.3.4 GLP-1 receptor-targeting peptides*

multi-use options such as SPECT, PET, and PRRT [72].

imaging studies have been studied to detect a GRPR and integrin αvβ3 dual targeting tracer 68Ga-BBN-RGD for PET/CT imaging of metastatic breast cancer [84]. Recent researches on BN analogues have focused on the DOTA chelating systems for

Neurotensin (NT) with 13 amino acids in its structure is expressed in the central nervous system, peripheral tissues, and gastrointestinal system [72]. Despite overexpression of neurotensin receptors in 75% of ductal pancreatic carcinomas, NT receptor expression of endocrine pancreatic tumors, pancreatitis, and normal pancreatic tissue is negative (somatostatin positive) [85]. In a clinical study using 111In-labeled DTPA and DOTA-conjugated NT analogues, a number of specific changes were made to unnatural amino acids, indicating that the C-terminus plays a key role in the binding and biological properties of the peptide, and there is not a critical change in receptor binding activity of the peptide [72]. Because of high renal involvement of 111In-NT analogues, PRRT is not considered appropriate with these analogues. With the discovery of three times more stable 99Tcm-labeled NT (NT-XIX) analogue, a better tumor-to-kidney ratio, higher tumor involvement, and higher kidney excretion were achieved. 99Tcm-Demotensin, which was a high-stability NT analogue, has a higher tumor-to-intestinal and tumor-to-liver ratios, but the most appropriate ratios for imaging pancreatic tumors were obtained with the 111In-labeled analogues [86].

It has been determined that in the majority of medullary thyroid carcinomas (MTCs), in a high rate of small-cell lung cancer patients, stromal ovarian cancers, astrocytomas, and some other tumor types have cholecystokinin-2 (CCK2) receptors. The CCK2 receptor-specific CCK peptide analogue was conjugated with DTPA for targeting this receptor [85]. The highest tumor uptake and too high renal involvement have been demonstrated at minigastrin analogues containing the CCK8 sequence. The addition of the histidine residues to the array almost reduces the kidney uptake by twofold. According to a study carried out in mice bearing the AR42J tumor, it was reported that the DOTA-conjugated HHEAYGWMDF peptide sequence exhibited the highest tumor-to-kidney ratio compared to all peptides studied [86]. Additionally, 99Tc-labeled N4-derived analogues of minigastrin have been synthesized [72]. Although studies with these radioligands are still in the

The glucagon-like peptide 1 (GLP-1) receptor which is overexpressed in human endocrine tumors, insulinomas, gastrinomas, and pheochromocytomas is a subtype of glucagon receptors used as a vehicle for in vivo tumor targeting. Because natural GLP-1 receptor agonists are metabolized quickly in the blood, a more stable and specific exendin peptide has been developed for use in the scintigraphic imaging of GLP-1 receptor-expressing tumors [72]. In the following years, 111In-DTPALys40 exendin-4 [72] and [Lys40 (Ahx-DTPA-111In) NH2] exendin-4 conjugates with high tumor-background ratios have been optimized with using animal models [87]. In a clinical study based on the development of GLP-1 receptor-targeting analogues, PET/CT imaging with the 68Ga-NOTA-exendin-4 peptide analogue has been reported to be a highly susceptible imaging technique for the detection of insuli-

initial stage for PRRT, they have significance features for the future.

*Peptide Synthesis*

distribution and imaging properties [79].

*4.1.3.1 GRP receptor-targeting peptides*

*4.1.3 Radionuclide therapy using other peptide analogues*

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

For clinical applications, it is preferred that the peptide analogues are metabolically stable. The natural structure of the peptides makes them sensitive to peptidase and rapidly breaks down in blood and other tissues, so their potential uses as radiopharmaceuticals are restricted. Strategies for stabilizing peptides include incorporating biologically insoluble peptide bonds, stabilized amino acid derivatives, and cyclization [70]. Although the stability is advantageous, it is necessary to keep the nuclide in the tumor area for a long period of time for a good target-to-nontarget ratios and to rapidly clear the nuclide from nontarget tissues and blood. Researches on the topic of peptide-based radiopharmaceuticals have mostly been focused on receptor agonists. However, in recent years, somatostatin and bombesin antagonist

Overexpression of gastrin-releasing peptide receptors (GRPR) is seen in many human tumors, including prostate and breast tumors. Bombesin (BN), a 14-amino acid peptide with high affinity to the GRP receptor, is used for GRP receptortargeted tumor imaging and treatment. 111In- and 99Tcm-labeled BN analogues have been improved for SPECT imaging of GRP receptors. After a while, a novel DTPA-bound BN analogue, [111In-DTPA-ACMpip5, Tha6, βAla11, Tha13, Nle14] BN (5–14) (Cmp 3), was synthesized. Replacement of the DTPA chelator in the 111In-Cmp3 analogue with a DOTA makes the compound suitable for therapeutic use and diagnostic PET imaging. Another promising peptide-conjugated DOTA is 177Lu-AMBA (DOTA-BN (7–14)), which exhibits good tumor-background ratios. The 177Lu-AMBA is excreted through the kidneys, but kidney excretion cannot be reduced by co-lysine injection because there is not any lysine in the peptide structure. Nowadays, it is the first choice in the targeting of 68Ga GRP receptors as a positron emitter radionuclide which provides shorter half-life and in-house radiolabeling procedures as well as more accurate high-resolution PET images. Recently,

peptide analogues have also been best shown for receptor targeting [72].

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imaging studies have been studied to detect a GRPR and integrin αvβ3 dual targeting tracer 68Ga-BBN-RGD for PET/CT imaging of metastatic breast cancer [84]. Recent researches on BN analogues have focused on the DOTA chelating systems for multi-use options such as SPECT, PET, and PRRT [72].
