Gastrin releasing peptide (GRP) receptor targeted radiopharmaceuticals: A concise update

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Abstract

The gastrin releasing peptide (GRP) receptor is becoming an increasingly attractive target for development of new radiolabeled peptides with diagnostic and therapeutic potential. The attractiveness of the GRP receptor as a target is based upon the functional expression of GRP receptors in several tumors of neuroendocrine origin including prostate, breast, and small cell lung cancer. This concise review outlines some of the efforts currently underway to develop new GRP receptor specific radiopharmaceuticals by employing a variety of radiometal chelation systems.

Introduction

For over a decade, the field of nuclear medicine has been investigating the potential of radiolabeled peptides to target tumor expression of receptors [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. The most outstanding example of success in this arena has been the results obtained targeting somatostatin receptor expression in the development of both diagnostic and therapeutic radiopharmaceuticals [1], [2], [12]. This work has paved the way for radiolabeled peptide exploration of other receptor systems including bombesin, alpha-melanocyte stimulating hormone, vasoactive intestinal peptide, cholecystokinin, and neurotensin [5], [6], [7], [8], [9], [10]. One recent focus of our laboratory, and others, has been the development of peptide based radiopharmaceuticals which target the mammalian gastrin releasing peptide (GRP) receptor, a subtype of the bombesin receptor family.

The bombesin receptor family is currently comprised of four receptor subtypes. These subtypes are classified as the neuromedin B (NMB) subtype (BB1), the GRP subtype (BB2), the orphan receptor subtype (BB3), and the bombesin (BBN) receptor subtype (BB4) [13], [14], [15], [16], [17], [18]. High affinity native peptide ligands for the BB1, BB2, and BB4 subtypes have been identified with the structures shown in Table 1. Although a high affinity native peptide ligand has not been identified for the BB3 subtype, a high affinity peptide which binds to the BB3 receptor has been synthesized [19]. Of the four known bombesin receptor subtypes, the BB2, or GRP subtype, has been studied the most extensively to date. Investigation of the bombesin receptor system was initiated in 1971 with the isolation of the tetradecapeptide bombesin from the skin of the frog Bombina bombina by Anastasi and co-workers [20]. The mammalian counterpart of bombesin, a 27 amino acid peptide called GRP was isolated from porcine stomach by McDonald and co-workers in 1979 [21]. GRP and bombesin share amidated C terminus sequence homology in the final 7 amino acids, -Trp-Ala-Val-Gly-His-Leu-Met-NH2.

The impetus for targeting the bombesin receptor system, and more specifically the GRP subtype, is based on reports demonstrating that a variety of human tumors and tumor cell lines have been shown to overexpress the GRP (BB2) receptor including prostate, breast, and small cell lung cancers [22], [23], [24], [25], [26].

With respect to human prostate cancer, high affinity GRP receptor expression has been identified in tissue biopsy samples and immortalized cell lines [27], [28], [29]. Markwalder and Reubi demonstrated that GRP receptor expression in primary prostatic invasive carcinoma was present in 100% of the tissues tested (30 of 30 cases). In 83% of these cases, GRP receptor expression was determined to be high or very high (>1000 dpm/mg). Of 26 patients studied with high-grade prostatic intraepithelial neoplasia, all but one demonstrated high to very high densities of GRP receptors. This study also demonstrated that more than 50% of androgen independent prostate cancer bone metastases were GRP receptor positive (4 of 7 cases). GRP receptor density analysis in non-neoplastic prostatic tissue, and in particular, benign prostatic hyperplasia was either completely absent or of low incidence. The study by Sun and co-workers further confirmed the preferential expression of GRP receptors in prostatic carcinoma with 91% of the samples tested (20 of 22) expressing mRNA for the GRP receptor [29]. Also of note in this study was the detection of mRNA for two other bombesin receptor subtypes, the NMB receptor and the orphan receptor BB3. Prior to human tissue analysis, both androgen-dependent and androgen-independent human prostate cancer cell lines were shown to express high affinity GRP receptors [30].

A large body of evidence is available demonstrating the expression of the GRP receptor subtype in estrogen receptor positive (ER+) and estrogen receptor negative (ER-) immortalized breast cancer cell lines [31], [32], [33], [34], [35], [36]. Two studies using primary human breast carcinoma and axillary metastastic tissue have confirmed the presence of the GRP receptor subtype, as well the expression of the GRP receptor gene in a large percentage of the tissues sampled [24], [33], [37]. Halmos and co-workers examined the binding of radioiodinated bombesin to a membrane preparation from 100 individual human breast carcinomas and found significant GRP receptor expression in 33% of these samples [33]. The study of Gugger and Reubi demonstrated that primary breast carcinomas had a 62% incidence (32 of 52 cases) of GRP receptor expression [24]. They further demonstrated 100% GRP receptor incidence in all lymph node metastases (n = 33) sampled from GRP receptor positive primary breast tumors. These results combined with those obtained in prostatic carcinoma tissue clearly make the GRP receptor an attractive candidate to target for diagnostic and therapeutic purposes.

This review highlights some of the more recent studies aimed at developing synthetic peptide analogues that exhibit specificity for the GRP preferring subtype of the bombesin receptor system. The results obtained with these systems demonstrate several rationales for formulation of new diagnostic and therapeutic radiopharmaceuticals targeting GRP receptor expression in neoplastic tissues.

Section snippets

Tc-99m/Re-188 bombesin conjugates

Technetium-99m continues to be at the forefront of nuclear medicinal applications due to its wide range availability (99Mo/99mTc generator system), ideal nuclear characteristics (t1/2 = 6.04h, Eγ = 140KeV (89%)), and well-established labeling chemistries. For example, 99mTc accounts for more than 85% of all diagnostic applications performed in medical facilities each year [38]. Rhenium-188 holds potential as an isotope for therapeutic nuclear medicinal applications primarily because of its

Trivalent radiometallated bombesin conjugates

Trivalent metallic radioisotopes, such as the radiolanthanides, are particularly attractive for use in diagnostic and/or therapeutic procedures in nuclear medicine. For example, the radiolanthanide and lanthanide-like (i.e., 90Y3+) elements possess similar chemistries in aqueous solution and can be produced as high specific activity reagents [57]. The radiolanthanides exist primarily in an oxidation state of 3+ and can be stabilized by hard donor atoms such as nitrogen or oxygen. The mechanism

Other metallated bombesin conjugates

Rhodium-105 continues to draw interest as a therapeutic radionuclide due to its availability (reactor-produced in high specific activity, [104Ru (n, γ) 105Ru(β) ⇒ 105Rh] and desirable physical characteristics (t1/2 = 1.4d, βmax = 0.57MeV). Ning and co-workers have reported the pharmacokinetic studies of numerous thioether-containing macrocycles with 105Rh [69]. The 105Rh-S4-BBN conjugate, (Fig. 1, Structure 11), has also been reported. The competitive binding displacement assay of Rh-S4

Conclusion

Radiolabeled, small, receptor-avid peptides continue to receive much interest toward the development of site-directed radiopharmaceuticals. The radiolabeled BBN conjugates discussed in this review have shown promising diagnostic/therapeutic efficacy toward the design of site-specific radiopharmaceuticals targeting cancer cells over-expressing the GRP receptor subtype. These studies provide important insight for identifying structural characteristics that are optimal for radiolabeled constructs

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