6-hydrazinopyridine-3-carboxylic-acid and tricine

A novel. micro-SPECT/CT imaging through

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Edetic Acid; Glycine; Humans; Hydrazines; Lung Neoplasms; Male; Mice; Mice, Nude; Nicotinic Acids; Organotechnetium Compounds; Proto-Oncogene Proteins c-met; Radiopharmaceuticals; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Transplantation, Heterologous

Several radiolabeled alpha-melanocyte stimulating hormone (α-MSH) analogs have been studied for their abilities to target melanoma tumor cells through specific recognition and binding to the melanocortin receptor 1 (MCR1). In this work, a lactam bridgecyclized α-MSH analog was labeled with (99m) via the hydrazinonicotinamide (HYNIC) chelator and characterized for its melanoma tumor targeting properties. The bifunctional chelating agent HYNIC-Boc was attached to the N-terminus of the MSH peptide followed by the lactam cyclization, resulting in the HYNIC-cyc-MSH analog. The lactam cyclized peptide displayed high affinity and specificity for MC1-receptors present on B16/F1 melanoma tumor cells, exhibiting an IC50 of 6.48 nM. HYNIC-cyc-MSH was radiolabeled with (99m)Tc using two common co-ligands, tricine and EDDA. In vitro, the radiochemical stability, cell binding and efflux properties were similar between the peptides radiolabeled with tricine and EDDA as co-ligands. In vivo, biodistribution studies (n=4) demonstrated that (99m)Tc- HYNIC-cyc-MSH/tricine had superior tumor to muscle and tumor to blood ratios than (99m)Tc-HYNIC-cyc-MSH/EDDA at early time points. Planar gamma imaging of melanoma bearing mice showed that 99mTc-HYNIC-cyc-MSH/tricine was able to clearly visualize tumors, underscoring the potential utility of (99m)Tc labeled lactam cyclized MSH molecules as melanoma imaging agents.

Topics: alpha-MSH; Animals; Chelating Agents; Diagnostic Imaging; Edetic Acid; Glycine; Hydrazines; Ligands; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Nicotinic Acids; Organotechnetium Compounds; Peptides; Protein Binding; Radiopharmaceuticals; Tissue Distribution

In this study, a new neurotensin (NT) analog was labeled with (99m) Tc via HYNIC chelator and tricine as coligand and investigated further. An NT (7-13) analog was prepared, and labeling with (99m) Tc was performed. The internalization rate and biodistribution of radiopeptide were studied in HT-29 cells and nude mice bearing tumor, respectively. Radiolabeling with (99m) Tc was performed at high specific activities (54 MBq/nmol) with an acceptable labeling yield (>95%). In vitro cell line studies showed a specific internalization uptake up to 13.23 ± 0.45% during 4 h which was blocked in the presence of excess cold peptide to 0.83 ± 0.15%. In biodistribution studies, uptake was observed in NT receptor-positive organs so that after 1 h the uptakes in mouse intestine and tumor were 1.23 ± 0.16% ID/g and 1.12 ± 0.11% ID/g, respectively. In animals co-injected with excess cold peptide, reduction uptake in tumor and intestines were 73% (1.10% vs. 0.29% ID/g at 4 h) and 61% (1.22% vs. 0.47% ID/g at 4 h) respectively. Predominant renal excretion pathway with a highest accumulation of activity in bladder was observed for this radiopeptide. This radiolabeled peptide could be a candidate for detection of NT positive tumors.

Topics: Animals; Glycine; HT29 Cells; Humans; Mice; Niacin; Organotechnetium Compounds; Peptides; Photons; Receptors, Neurotensin

Ubiquicidin (UBI) 29-41 is a cationic synthetic antimicrobial peptide fragment that binds preferentially with the anionic microbial cell membrane at the site of infection. This study was conducted to evaluate the potentiality of [(99m)Tc/Tricine/HYNIC(0)]UBI 29-41 prepared from lyophilized kits as an infection imaging agent in humans.. Seven patients (5 males and 2 females; mean age=55 years; age range=35-75 years) with suspected bone or soft-tissue infections participated in this study. [(99m)Tc/Tricine/HYNIC]UBI 29-41, corresponding to activity in the range 555-740 MBq added to 40 mug of peptide obtained from instant freeze-dried kit formulations with radiochemical purities >95%, was injected intravenously. A 45-min dynamic study was followed by spot views of the suspected region of infection (target) and a corresponding normal area (nontarget). Whole-body anterior and posterior images were also acquired at 30, 60 and 120 min after injection. True- or false-positive or true- or false-negative images were interpreted upon bacterial culture, radiography, clinical tests and bone scanning.. The biodistribution of [(99m)Tc/Tricine/HYNIC]UBI 29-41 in patients showed rapid accumulation of activity in the kidneys in the first 30 min after injection that gradually declined and accumulated in the urinary bladder. There were positive findings in five studies and negative findings in two. Findings were subsequently confirmed to be true positive or negative. Images showed minimal accumulation in nontarget tissues, with an average target/nontarget ratio of 2.10+/-0.33 in positive lesions at 30 min.. Given its favorable clinical characteristics, [(99m)Tc/Tricine/HYNIC]UBI 29-41 shows promise as a tracer for infection imaging that allows early diagnosis (30 min) of infection.

Topics: Adult; Aged; Antimicrobial Cationic Peptides; Bacterial Infections; Female; Glycine; Humans; Hydrazines; Male; Middle Aged; Nicotinic Acids; Organotechnetium Compounds; Peptide Fragments; Quality Control; Radionuclide Imaging; Radiopharmaceuticals; Soft Tissue Infections; Tissue Distribution

In previous studies we demonstrated that lipophilic (99m)Tc-labeled LTB4 antagonist 1 (RP517) accumulated in infectious foci in rabbits, but hepatobiliary clearance hampered imaging of abdominal lesions. We now report the use of cysteic acid as a pharmacokinetic modifier to improve the water solubility and renal clearance of three hydrophilic analogues of 1. Divalent LTB4 antagonist 17 (DPC11870-11) is a DTPA conjugate for radiolabeling with In-111. Monovalent LTB4 antagonists 15 (BMS57868-88) and divalent LTB4 antagonist 18 (BMS57868-81) are conjugated to bifunctional chelator HYNIC for radiolabeling with (99m)Tc. The three compounds labeled efficiently with 111In or (99m)Tc with high radiochemical purity and specific activities. Scintigraphic images obtained in New Zealand White rabbits having acute intramuscular E. coli infection demonstrated that all agents were able to clearly visualize the abscess, and clearance was exclusively renal. The biodistribution of the (99m)Tc-labeled LTB4 antagonists was affected by the coligands used with the HYNIC chelator and by the monovalent or divalent nature of the receptor binding moiety. The best scintigraphic images were obtained with monovalent HYNIC conjugate 15 using tricine and isonicotinic acid as coligands with HYNIC for coordination with (99m)Tc.

Topics: Abscess; Animals; Binding, Competitive; Chelating Agents; Escherichia coli Infections; Female; Glycine; Granulocytes; Humans; Hydrazines; In Vitro Techniques; Indium Radioisotopes; Isonicotinic Acids; Isotope Labeling; Leukotriene B4; Muscle, Skeletal; Nicotinic Acids; Organotechnetium Compounds; Rabbits; Radioligand Assay; Radiopharmaceuticals; Solubility; Structure-Activity Relationship; Tissue Distribution

The level of alpha(V)beta(3) integrins on endothelial cells is elevated in angiogenesis. The high binding specificity to alpha(V)beta(3) integrins of peptides containing Arg-Gly-Asp (RGD) residues suggests that the radiolabeled RGD peptides may be useful as tumor specific imaging agents. In this research, cyclised peptides containing Arg-Gly-Asp (RGD) and Arg-Gly-Glu (RGE, as control) residues were conjugated with HYNIC and labeled with (99m)Tc.. The goal was to evaluate the influence of co-ligand, either tricine or ethylenediamine-N,N'-diacetic acid (EDDA) on protein and integrin binding and on cellular uptake in culture.. The n-octanol/water partition coefficient, binding to bovine serum albumin (BSA) and human umbilical vein endothelial (HUVE) cells, and cell lysate distributions of the radiolabeled peptides were evaluated.. The co-ligands had a significant effect on the labeling efficiency of the HYNIC conjugates and on certain properties of the (99m)Tc complexes. The labeling efficiency with tricine was 10 fold higher and BSA binding was over 8 fold greater compared to EDDA. Both RGD labels showed higher (6 to 28 fold) binding to HUVE cells than that of the RGE labels, indicating binding specificity. After cell-lysis, only a small percentage of the total RGD label that accumulated in the cells was found bound to cellular proteins (9% of RGD/tricine and 5% of RGD/EDDA), implying that over 90% of the radiolabeled peptides were internalized for both radiolabeled RGDs. The number of the RGD molecules bound to proteins was estimated to be approximately three per cell, suggesting that only a small number of alpha(V)beta(3) integrin proteins are expressed on the cells.. Apart from the differences in radiolabeling, the only important effect of substituting EDDA for tricine as co-ligand on the HYNIC-peptides was the lower degree of serum protein binding. In spite of the lower serum protein binding potential, in vivo tumor accumulation of the RGD/EDDA may not be improved compared to RGD/tricine since quantitation of the cell binding results suggests that the number of alpha(V)beta(3) integrin proteins per cell might be limited.

Topics: Blood Proteins; Cells, Cultured; Edetic Acid; Endothelium, Vascular; Glycine; Humans; Hydrazines; Integrins; Ligands; Metabolic Clearance Rate; Nicotinic Acids; Oligopeptides; Protein Binding; Radionuclide Imaging; Radiopharmaceuticals; Technetium; Umbilical Veins