Technetium-99m RP527, a GRP analogue for visualisation of GRP receptor-expressing malignancies: a feasibility study

Abstract

Gastrin-releasing peptide (GRP) receptor scintigraphy could allow prediction of response to GRP receptor-targeted treatment options, early non-invasive diagnosis and in vivo prognostic stratification of GRP receptor-positive tumours. This study reports on the imaging characteristics and efficacy for tumour detection of technetium-99m RP527, a 99mTc chelated targeting peptide derived from bombesin, which binds GRP receptors with high affinity. Ten patients (four men and six women, mean age 56.4 years) either suffering from metastasised prostate (n, number of patients = 4) or breast carcinoma (n=1) or presenting with a clinical diagnosis highly suggestive for breast carcinoma (n=5) were included in the study. In the latter five patients, 99mTc-RP527 scintigraphy was performed prior to diagnostic, e.g. biopsy, and staging examinations. Final diagnosis in these patients was breast carcinoma in all five. In all patients, whole-body planar scans and tomographic images were acquired 1 h and 5-6 h post injection of 555 MBq 99mTc-RP527 and tumour to normal tissue (T/N) ratios determined. 99mTc-RP527 showed specific uptake in four of six breast and one of four prostate carcinomas. T/N ratios derived from planar and tomographic images increased significantly (P<0.01) from 1.65 (SD 1.53) and 3.35 (SD 3.04) to 2.58 (SD 1.26) and 7.23 (SD 8.46), respectively. T/N ratios derived from tomographic images were consistently higher (P<0.01). The data presented suggest that 99mTc-RP527 results in specific tumour localisation and exhibits good imaging characteristics with a good T/N ratio that may be further enhanced by single-photon emission tomography.

Synthesis and Characterization of a High-Affinity NOTA-Conjugated Bombesin Antagonist for GRPR-Targeted Tumor Imaging

“…Bombesin analog NOTA-PEG 2 -[D-Phe 6 ,Sta 13 ,Leu 14 ]bombesin [6][7][8][9][10][11][12][13][14] (further denoted as NOTA-P2-RM26, see Chart) was synthesized by standard manual solid-phase peptide synthesis 17 as described in Supplementary material 1.…”

Effective treatment of experimental U-87MG human glioblastoma in nude mice with a targeted cytotoxic bombesin analogue, AN-215

“…in the circulation, which can release the cytotoxic radical before the targeting is completed . Preclinical and clinical results with new radioligands, developed for BN-receptor scintigraphy, also indicate that BN analogues can accumulate in BN receptor-positive tumours, further supporting the theory that BN receptors can be used for targeted chemotherapy (Breeman et al, 1999;Van de Wiele et al, 2000).…”

Synthesis of bombesin-functionalized iron oxide nanoparticles and their specific uptake in prostate cancer cells

“…In fact, there have been various radiolabeled bombesin conjugates containing extensive modifications to the N-terminus, which still retain high affinity for the desired receptors (Baidoo et al 1998;La Bella et al 2002;Smith et al 2003; Van de Wiele et al 2001). Consequently, most labeled bombesin analogs are simply modifications of this bombesin-(7-14) sequence (Baidoo et al 1998;La Bella et al 2002;Smith et al 2003; Van de Wiele et al 2001; Van de Wiele et al 2000). In this case, modification of the bombesin-(7-14) peptide was carried out to include a second β-alanine extension in position six, replacing the non-essential D-Tyr (Fig.…”

“…The peptide analog [D-Tyr6, β-Ala11, Phe13, Nle14]bombesin-(6-14) is a universal bombesin ligand, which has been shown to bind to all four GRP receptor sub-types with high affinity (Mantey et al 1997;Pradhan et al 1998;Van de Wiele et al 2000). The GRP family of receptors are known to be over-expressed in a variety of human tumors, including prostate cancer, making the pan-bombesin peptide a potentially important targeting entity for both cancer diagnosis and treatment (Patel et al 2006;Sun et al 2000).…”

“…Radionuclide probes based on bombesin, an amphibian tetradecapeptide, have been reported to specifically target GRP overexpressing tumors (Hoffman et al 2003;Van de Wiele et al 2000). Four different receptor sub-types were discovered for the GRP family of peptides: GRP-R, neuromedin-B receptor (NMB-R), BRS-3, and BB4-R. A very potent ligand for all four bombesin receptor sub-types was previously reported, with a structure of [D-Tyr6, β-Ala11, Phe13, Nle14]bombesin-(6-14) (Mantey et al 1997;Pradhan et al 1998;Reubi et al 2002).…”