Design and synthesis of a bombesin peptide-conjugated tripodal phosphino dithioether ligand topology for the stabilization of the fac-[M(CO)3]+ core (M=(99 m)Tc or Re).

A new tumor-seeking tridentate topology consisting of a phosphino dithioether ((HOCH(2))(2)PCH(2)CH(2)S(CH(2))(n)CH(2)SR; PS(2)) ligand framework for the production of kinetically inert and in vivo stable facial [(99m)Tc(CO)(3)(PS(2))](+) or [Re(CO)(3)(PS(2))](+) is described. The X-ray crystal structure of fac-Re(CO)(3)(PS(2))PF(6) is reported. The bioconjugation strategies for incorporating bombesin (BBN) peptides on to the PS(2) tripodal framework and, thereby, de novo designing of GRP receptor-seeking Tc(PS(2)-BBN)(CO)(3) are developed.

Comparative evaluation of three 64Cu-labeled E. coli heat-stable enterotoxin analogues for PET imaging of colorectal cancer.

Analogues of the E. coli heat-stable enterotoxin (STh) are currently under study as both imaging and therapeutic agents for colorectal cancer. Studies have shown that the guanylate cyclase C (GC-C) receptor is commonly expressed in colorectal cancers.

In vivo imaging of human colorectal cancer using radiolabeled analogs of the uroguanylin peptide hormone.

Background: Uroguanylin is an endogenous peptide agonist that binds to the guanylate cyclase C receptor (GC-C). GC-C is overexpressed in human colorectal cancer (CRC), and exposure of GC-C-expressing cells to GC-C agonists results in cell cycle arrest and/or apoptosis, highlighting the therapeutic potential of such compounds. This study describes the first use of radiolabeled uroguanylin analogs for in vivo detection of CRC.

TLD assessment of mouse dosimetry during microCT imaging.

Advances in laboratory animal imaging have provided new resources for noninvasive biomedical research. Among these technologies is microcomputed tomography (microCT) which is widely used to obtain high resolution anatomic images of small animals. Because microCT utilizes ionizing radiation for image formation, radiation exposure during imaging is a concern.

Evaluation of the pharmacokinetic effects of various linking group using the 111In-DOTA-X-BBN(7-14)NH2 structural paradigm in a prostate cancer model.

The high incidence of BB2 receptor (BB2r) expression in various cancers has prompted investigators to pursue the development of BB2r-targeted agents for diagnostic imaging, chemotherapy, and radiotherapy. Development of BB2r-targeted agents, based on the bombesin (BBN) peptide, has largely involved the use of the bifunctional chelate approach in which the linking group serves several key roles including pharmacokinetic modification. Understanding the in vivo properties of the various pharmacokinetic modifying linking groups is crucial for developing BB2r-targeted agents with improved targeting and clearance characteristics.

In vivo evaluation and small-animal PET/CT of a prostate cancer mouse model using 64Cu bombesin analogs: side-by-side comparison of the CB-TE2A and DOTA chelation systems.

Unlabelled: The BB2 receptor subtype, of the bombesin family of receptors, has been shown to be highly overexpressed in a variety of human tumors, including prostate cancer. Bombesin (BBN), a 14-amino acid peptide, has been shown to target the BB2 receptor with high affinity. 64Cu (half-life = 12.

In vitro and in vivo evaluation of Alexa Fluor 680-bombesin[7-14]NH2 peptide conjugate, a high-affinity fluorescent probe with high selectivity for the gastrin-releasing peptide receptor.

Gastrin-releasing peptide (GRP) receptors are overexpressed on several types of human cancer cells, including breast, prostate, small cell lung, and pancreatic cancers. Bombesin (BBN), a 14-amino acid peptide that is an analogue of human GRP, binds to GRP receptors with very high affinity and specificity. The aim of this study was to develop a new fluorescent probe based on BBN having high tumor uptake and optimal pharmacokinetics for specific targeting and optical imaging of human breast cancer tissue.

Selective targeting of E. coli heat-stable enterotoxin analogs to human colon cancer cells.

Background: Radiolabeled analogs of the E. coli heat-stable enterotoxin (ST(h)) are currently under study as imaging and therapeutic agents for colorectal cancer. The aim of these studies is to compare in vitro and in vivo characteristics of two novel ST(h) analogs with appended DOTA chelating moieties.

Microimaging characterization of a B16-F10 melanoma metastasis mouse model.

Metastatic mouse models of melanoma have been characterized by gross necropsy examination, histopathology, and optical imaging. To determine if the time progression, extent, and metabolism of melanoma metastases could be monitored noninvasively, serial micro-CT and small-animal PET imaging studies were performed by using a mouse model of melanoma. Juvenile female C57BL/6 mice were injected intravenously with syngenic B16-F10 melanoma cells.

In vitro and in vivo evaluation of 111In-labeled E. coli heat-stable enterotoxin analogs for specific targeting of human breast cancers.

Research into the interaction between the E. coli heat-stable enterotoxin (STh) and the guanylin receptor guanylate cyclase C (GC-C) has generated >100 synthetic analogs of the peptide, several of which have been investigated as imaging or therapeutic agents for colorectal cancers. The evidence presented here suggests that in addition to STh binding to GC-C expressing cell lines derived from human colon, STh also specifically binds to an as yet unidentified receptor expressed in high densities on the surface of cell lines derived from human breast cancers.

In vitro and in vivo evaluation of 177Lu- and 90Y-labeled E. coli heat-stable enterotoxin for specific targeting of uroguanylin receptors on human colon cancers.

The human E. coli heat-stable enterotoxin (ST(h), amino acid sequence N1SSNYCCELCCNPACTGCY19) binds specifically to the guanylate cyclase C (GC-C) receptor, which is present in high density on the apical surface of normal intestinal epithelial cells as well as on the surface of human colon cancer cells. Analogs of ST(h) are currently being used as vectors targeting human colon cancers.

Evaluation of combined (177)Lu-DOTA-8-AOC-BBN (7-14)NH(2) GRP receptor-targeted radiotherapy and chemotherapy in PC-3 human prostate tumor cell xenografted SCID mice.

The focus of this study was to evaluate the therapeutic benefit of combined gastrin-releasing peptide (GRP) receptor-targeted radiotherapy (TRT) with chemotherapy, using the PC-3 xenograft severe combined immunodeficiency (SCID) mouse model. (177)Lu-DOTA-8-AOC-BBN(7-14)NH(2) is a radiotherapeutic peptide that specifically targets the gastrin-releasing peptide receptor overexpressed on primary and metastatic prostate cancer. The chemotherapeutic agents, docetaxel and estramustine, were administered as single agents or in combination with the receptor-targeted radiotherapeutic agent.

Radiolabeled peptide conjugates for targeting of the bombesin receptor superfamily subtypes.

Research laboratories around the world are currently focusing their efforts toward the development of radiometallated, site-directed, diagnostic/therapeutic agents based upon small peptides such as octreotide, neurotensin, alpha-melanocyte stimulating hormone, vasointestinal peptide and others. Bombesin (BBN) or derivatives of bombesin are also of significant interest. Bombesin is a 14-amino-acid peptide with very high affinity for the BB2 or gastrin-releasing peptide receptor (GRPr).

Evaluation of beta-absorbed fractions in a mouse model for 90Y, 188Re, 166Ho, 149Pm, 64Cu, and 177Lu radionuclides.

Several short-lived, high-energy beta emitters are being proposed as the radionuclide components for molecular- targeted potential cancer therapeutic agents. The laboratory mice used to determine the efficacy of these new agents have organs that are relatively small compared to the ranges of these high-energy particles. The dosimetry model developed by Hui et al.

In vitro and in vivo comparison of human Escherichia coli heat-stable peptide analogues incorporating the 111In-DOTA group and distinct linker moieties.

Three human Escherichia coli heat-stable peptide (STh) analogues, each containing a DOTA chelating group, were synthesized by SPPS and oxidative refolding and compared in in vitro and in vivo systems. One analogue, DOTA-F19-STh(1-19), contains an N-terminal DOTA group attached via an amide bond linkage to an STh moiety which is essentially wild-type except for a Tyr to Phe alteration at position 19 of the molecule. A second analogue, DOTA-R1,4,F19-STh(1-19), differs from the first in that asparagine residues in positions 1 and 4 have been altered to arginine residues in order to examine the effect of positively charged groups in the linker domain.

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

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.

Radiochemical investigations of gastrin-releasing peptide receptor-specific [(99m)Tc(X)(CO)3-Dpr-Ser-Ser-Ser-Gln-Trp-Ala-Val-Gly-His-Leu-Met-(NH2)] in PC-3, tumor-bearing, rodent models: syntheses, radiolabeling, and in vitro/in vivo studies where Dpr = 2,3-diaminopropionic acid and X = H2O or P(CH2OH)3.

Bombesin (BBN), a 14 amino acid peptide, is an analogue of human gastrin-releasing peptide (GRP) that binds to GRP receptors (GRPrs) with high affinity and specificity. The GRPr is overexpressed on a variety of human cancer cells, including prostate, breast, lung, and pancreatic cancers. The specific aim of this study was to develop (99m)Tc(I)-radiolabled BBN analogues that maintain high specificity for the GRPr in vivo.

Syntheses, in vitro and in vivo characterization of a 99mTc-(I)-tricarbonyl-benzylamino-dihydroxymethyl phosphine (NP(2)) chelate.

Studies were performed to study the complexation chemistry of 99mTc(CO)(+)(3) with a new tridentate amino-dihydroxymethyl phosphine (NP(2)) ligand with the 99mTc(CO)(3)(OH(2))(+)(3) synthon at tracer levels. A single, well-defined 99mTc(CO)(3)NP(2) complex is formed at pH 7.5 within 10 min at 60 degrees C that exhibits high in vitro and in vivo stability.

Novel series of 111In-labeled bombesin analogs as potential radiopharmaceuticals for specific targeting of gastrin-releasing peptide receptors expressed on human prostate cancer cells.

Unlabelled: Gastrin-releasing peptide (GRP) receptors have been shown to be expressed with high densities on several types of cancer cells including prostate, breast, small cell lung, and pancreas cancers. Bombesin (BBN) has been known to bind to GRP receptors with high affinity and specificity. The aim of these studies was to develop new (111)In-labeled BBN analogs having high tumor uptake and optimal pharmacokinetics for specific targeting of human prostate cancers.

Radiochemical investigations of [188Re(H2O)(CO)3-diaminopropionic acid-SSS-bombesin(7-14)NH2]: syntheses, radiolabeling and in vitro/in vivo GRP receptor targeting studies.

Background: Bombesin (BBN), a 14 amino acid peptide, is an analogue of human gastrin-releasing peptide (GRP) that binds to GRP receptors (GRPr) with high affinity and specificity. The GRPr is over-expressed on a variety of human cancer cells including prostate, breast, lung, and pancreatic cancers. The specific aim of this study was to develop a 188Re(I)-radiolabeled BBN analogue that maintains high specificity for the GRPr in vivo.

In vitro and in vivo antitumor properties of tetrakis((trishydroxy- methyl)phosphine)gold(I) chloride.

A novel hydrophilic gold compound, tetrakis((trishydroxymethyl)phosphine)gold(I) chloride 1, has been investigated for its antitumor properties. In vitro studies demonstrate that 1 is active against HCT-15, AGS, PC-3, and LNCaP tumor cells. Cell cycle analysis of the HCT-15 cells by flow cytometry revealed elongation of the G1 phase of the cell cycle leading to growth inhibition.

Radiochemical investigations of 177Lu-DOTA-8-Aoc-BBN[7-14]NH2: an in vitro/in vivo assessment of the targeting ability of this new radiopharmaceutical for PC-3 human prostate cancer cells.

Bombesin (BBN), a 14 amino acid peptide, is an analogue of human gastrin releasing peptide (GRP) that binds to GRP receptors (GRPr) with high affinity and specificity. The GRPr is over expressed on a variety of human cancer cells including prostate, breast, lung, and pancreatic cancers. The specific aim of this study was to identify a BBN analogue that can be radiolabeled with (177)Lu and maintains high specificity for GRPr positive prostate cancer tumors in vivo.

Radiochemical investigations of (99m)Tc-N(3)S-X-BBN[7-14]NH(2): an in vitro/in vivo structure-activity relationship study where X = 0-, 3-, 5-, 8-, and 11-carbon tethering moieties.

Bombesin (BBN), a 14 amino acid peptide, is an analogue of human gastrin releasing peptide (GRP) that binds to GRP receptors (GRPr) with high affinity and specificity. The GRPr is overexpressed on a variety of human cancer cells, including prostate, breast, lung, and pancreatic cancers. The specific aim of this study was to develop (99m)Tc-radiolabeled BBN analogues that maintain high specificity for the GRPr in vivo.