gastrin-releasing-peptide and 1-4-7-10-tetraazacyclododecane--1-4-7-10-tetraacetic-acid

Neuroendocrine differentiation of prostate cancer (PCa) is a relatively frequent event, generally understudied, that carries important prognostic information. It is the most frequently observed during the advanced stages of disease, when PCa has lost its sensitivity to androgen deprivation therapy or to chemotherapy, moderate to diffuse bone metastatic spread dominates the imaging scenario and it is responsible for painful clinical symptomatology. However, evidences indicate that neuroendocrine differentiation is a progressive phenomenon that starts at the very early part of the pathogenesis of cancer transformation contributing to it. Neuroendocrine tumor phenotypes have reduced capability to secrete the prostate specific antigen (PSA) and therefore PSA does not represent a reliable marker to follow-up neuroendocrine differentiation. Tumor progression may be monitored by measuring plasma concentration of neuroendocrine tumor markers, primarily chromogranin A and neuron-specific enolase. Several nuclear medicine tracers are available for studying different biochemical properties of tumor cells with neuroendocrine differentiation. Single photon computed emission tomography (SPECT) with [111In-diethylenetriaminepentaacetic acid] ([111In-DTPA0])- octreotide (Octreoscan) has been extensively used in the past. However, the development of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), which in comparison to DTPA allows higher affinity bindings for beta-emitting radionuclides and for somatostatin (SST) analogues, and the increased availability of the Germanium-68/Gallium-68 (68Ge/68Ga)-generator, which enables positron emission tomography/computed tomography (PET/CT) imaging, have allowed the synthesis of several PET tracers for different SST receptors. The receptor of the bombesin/ gastrin releasing peptide (GRP), which is overexpressed in PCa with neuroendocrine differentiation, also represents an innovative research field with diagnostic and therapeutic applications through, respectively, positron and beta emitters. At the moment, however, we observe some discrepancy between the high number of preclinical studies and the small number of clinical studies, most likely related to competing and, at the moment, more effective radiopharmaceuticals for imaging and for radiometabolic therapy, such PET/CT with radiolabeled choline and prostate-specific membrane antigene (PSMA)-ligands, the latter being labeled either with 68Ga for imagin

Topics: Bombesin; Gallium Radioisotopes; Gastrin-Releasing Peptide; Germanium; Heterocyclic Compounds, 1-Ring; Humans; Male; Neuroendocrine Tumors; Pentetic Acid; Phenotype; Positron Emission Tomography Computed Tomography; Prostatic Neoplasms; Radioisotopes; Radiopharmaceuticals; Somatostatin; Tomography, Emission-Computed, Single-Photon

In the present study we demonstrate the in vitro and in vivo comparison of the (44)Sc and (68)Ga labeled DOTA-BN[2-14]NH(2). (44)Sc is a positron emitter with a half life of 3.92 h. Hence it could be used for PET imaging with ligands requiring longer observation time than in the case of (68)Ga.. The binding affinity of (nat)Sc-DOTA-BN[2-14]NH(2) and (nat)Ga-DOTA-BN[2-14]NH(2) to GRP receptors was studied in competition to [(125)I-Tyr(4)]-Bombesin in the human prostate cancer cell line PC-3. A preliminary biodistribution in normal rats was performed, while first microPET images were assessed in male Copenhagen rats bearing the androgen-independent Dunning R-3327-AT-1 prostate cancer tumor.. The affinity to GRP receptors in the PC-3 cell line was higher for (nat)Ga-DOTA-BN[2-14]NH(2) (IC(50)(nM)=0.85 ± 0.06) than that of (nat)Sc-DOTA-BN[2-14]NH(2) (IC(50) (nM)=6.49 ± 0.13). The internalization rate of (68)Ga labeled DOTA-BN[2-14]NH(2) was slower than that of (44)Sc, but their final internalization percents were comparable. (68)Ga-DOTA-BN[2-14]NH(2) was externalized faster than (44)Sc-DOTA-BN[2-14]NH(2). The biodistribution of (44)Sc-DOTA-BN[2-14]NH(2) and (68)Ga-DOTA-BN[2-14]NH(2) in normal rats revealed a higher uptake in target organs and tissues of the first one while both excreted mainly through urinary tract. In microPET images both tracers were accumulated in the tumor with similar uptake patterns.. Despite the differences in the receptor affinity both the (68)Ga- and the (44)Sc-labeled DOTA-BN[2-14]NH(2) tracers showed comparable distribution and similar time constants of uptake and elimination. Moreover no differences in tumor accumulation (neither in the overall uptake nor in the dynamics) were observed from the microPet imaging. From that perspective the use of either (44)Sc or (68)Ga for detecting tumors with GRP receptors is equivalent.

Topics: Animals; Bombesin; Cell Line, Tumor; Gallium Radioisotopes; Gastrin-Releasing Peptide; Heterocyclic Compounds, 1-Ring; Humans; Male; Positron-Emission Tomography; Prostatic Neoplasms; Radioisotopes; Radiopharmaceuticals; Rats; Scandium; Tissue Distribution

Bombesin (BBN) is a peptide showing high affinity for the gastrin-releasing peptide receptor. Tumors such as prostate, small cell lung cancer, breast, gastric, and colon cancer are known to over express receptors to BBN and gastrin-releasing peptide (GRP). The goal of this study was to evaluate a new (67)Ga radiolabeled BBN analog based on the bifunctional chelating ligand DOTA (1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid), which could be used as a tool for diagnosis of GRP receptor-positive tumors. DOTA-GABA-BBN (7-14) NH(2) was synthesized using a standard Fmoc strategy. Labeling with (67)Ga was performed at 95°C for 30 minutes in ammonium acetate buffer (pH = 4.8). Radiochemical analysis involved ITLC and HPLC methods. The stability of radiopeptide was examined in the presence of human serum at 37°C up to 24 hours. The receptor-bound internalization and externalization rates were studied in GRP receptor expressing PC-3 cells. Biodistribution of radiopeptide was studied in nude mice bearing PC-3 tumor. Labeling yield of >90% was obtained corresponding to a specific activity of approximatrly 2.6 MBq/nmol. Peptide conjugate showed good stability in the presence of human serum. The radioligand showed a good and specific internalization into PC-3 cells (16.13% ± 0.71% at 4 hours). After 4 hours, a considerable amount of activity (52.42% ± 1.86%) was externalized. In animal biodistribution studies, a receptor-specific uptake of radioactivity was observed in GRP-receptor-positive organs. After 4 hours, the uptake in mouse tumor and pancreas was 1.30% ± 0.18% ID/g (percentage of injected dose per gram of tissue) and 1.21% ± 0.13% ID/g, respectively. These data show that [(67)Ga]-DOTA-GABA-BBN (7-14) NH₂ is a specific radioligand for GRP receptor positive tumors and is a suitable candidate for clinical studies.

Topics: Animals; Bombesin; Cell Line, Tumor; Chelating Agents; Chromatography, High Pressure Liquid; Drug Evaluation, Preclinical; gamma-Aminobutyric Acid; Gastrin-Releasing Peptide; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 1-Ring; Humans; Hydrogen-Ion Concentration; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Chemical; Neoplasms; Peptides; Receptors, Bombesin; Tissue Distribution; Tomography, Emission-Computed, Single-Photon