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1.
Nucl Med Commun ; 33(1): 69-79, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21970835

ABSTRACT

OBJECTIVES: Gastroenteropancreatic neuroendocrine tumors (NETs) are cancers originating from neuroendocrine organs such as the pancreas, pituitary, thyroid, and adrenal glands and tumors arising from the diffuse neuroendocrine cells that are widely distributed throughout the body. NETs express somatostatin (SS) and contain a high density of SS receptors; therefore, they can be specifically targeted with SS-based radiopharmaceuticals. The aim of this research was to determine the validity in terms of specificity, sensitivity, and the agreement beyond chance with the biopsy (gold standard) of the 99mTc-EDDA-HYNIC-Tyr³octreotide (99mTc-TOC) to image and localize NETs and their metastases. MATERIALS AND METHODS: Freeze-dried kits containing 0.0125 mg HYNIC-octreotide and co-ligands were easily labeled and quality controlled within the hospital radiopharmacy. Fifty-six consecutive Mexican patients with a previous presumptive diagnosis of NETs underwent several clinical and laboratory studies and were referred to the Nuclear Medicine Department for a routine scan with 99mTc-TOC. The patients were injected with 500-600 MBq 99mTc-TOC, and whole-body images were obtained 2 h later with a SPECT or a SPECT/CT camera. Two nuclear medicine physicians observed the images and classified them as 17 negative and 39 positive. After correlating the image of each patient with our 'gold standard' (biopsy, clinical history, morphological images, and tumor marker assays), the 99mTc-TOC images were classified by the same two physicians as 12 true negatives, five false negatives, 38 true positives and one false positive. RESULTS: The validity of 99mTc-TOC in terms of relative frequencies with corresponding 95% confidence intervals were as follows: 92.3% (64-100%) specificity; 88.4% (78-97%) sensitivity; and the agreement beyond chance was 73% (60-84%). The positive predictive value was 97.4% (87-100%); the negative predicted value was 70.6% (48-93%); the accuracy was 89.3% (89-97%); and the prevalence was 76.8% (64-87%). CONCLUSION: Because of these high values, we strongly recommend scintigraphy with the Mexican-produced 99mTc-TOC for the localization of NETs and their metastases, and we conclude that it is a good tool for detecting neuroendocrine disease in a Mexican population.


Subject(s)
Digestive System Neoplasms/diagnostic imaging , Multimodal Imaging/methods , Neuroendocrine Tumors/diagnostic imaging , Organotechnetium Compounds , Positron-Emission Tomography , Radiopharmaceuticals , Tomography, Emission-Computed, Single-Photon/methods , Tomography, X-Ray Computed , Adult , Aged , Aged, 80 and over , Digestive System Neoplasms/secondary , Female , Humans , Male , Middle Aged , Neuroendocrine Tumors/secondary , Reproducibility of Results , Sensitivity and Specificity , Whole Body Imaging , Young Adult
2.
Nucl Med Biol ; 38(1): 1-11, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21220124

ABSTRACT

UNLABELLED: The aim of this research was to prepare a multifunctional system of technetium-99m-labelled gold nanoparticles conjugated to HYNIC-GGC/mannose and to evaluate its biological behaviour as a potential radiopharmaceutical for sentinel lymph node detection (SLND). METHODS: Hydrazinonicotinamide-Gly-Gly-Cys-NH(2) (HYNIC-GGC) peptide and a thiol-triazole-mannose derivative were synthesized, characterized and conjugated to gold nanoparticles (AuNP, 20 nm) to prepare a multifunctional system of HYNIC-GGC-AuNP-mannose by means of spontaneous reaction of the thiol (Cys) present in HYNIC-GGC sequence and in the thiol-mannose derivative. The nanoconjugate was characterized by transmission electron microscopy (TEM), IR, UV-Vis, Raman, fluorescence and X-ray photoelectron spectroscopy (XPS). Technetium-99m labelling was carried out using EDDA/tricine as coligands and SnCl(2) as reducing agent with further size-exclusion chromatography purification. Radiochemical purity was determined by size-exclusion HPLC and ITLC-SG analyses. In vitro binding studies were carried out in rat liver homogenized tissue (mannose-receptor positive tissue). Biodistribution studies were accomplished in Wistar rats and images obtained using a micro-SPECT/CT system. RESULTS: TEM and spectroscopy techniques demonstrated that AuNPs were functionalized with HYNIC-GGC-NH(2) and thiol-mannose through interactions with thiol groups and the N-terminal amine of cysteine. Radio-chromatograms showed radiochemical purity higher than 95%. (99m)Tc-EDDA/HYNIC-GGC-AuNP-mannose ((99m)Tc-AuNP-mannose) showed specific recognition for mannose receptors in rat liver tissue. After subcutaneous administration of (99m)Tc-AuNP-mannose in rats (footpad), radioactivity levels in the popliteal and inguinal lymph nodes revealed that 99% of the activity was extracted by the first lymph node (popliteal extraction). Biodistribution studies and in vivo micro-SPECT/CT images in Wistar rats showed an evident lymph node uptake (11.58 ± 1.98 %ID at 1 h) which was retained during 24 h with minimal kidney accumulation (0.98 ± 0.10 %ID) and negligible uptake in all other tissues. CONCLUSIONS: This study demonstrated that (99m)Tc-AuNP-mannose remains within the first lymph node during 24 h and therefore might be useful as a target-specific radionanoconjugate for SLND using "1-day" or "2-day" conventional protocols.


Subject(s)
Gold/chemistry , Lymph Nodes/metabolism , Mannose/metabolism , Metal Nanoparticles/chemistry , Oligopeptides/chemistry , Oligopeptides/metabolism , Organotechnetium Compounds/chemistry , Animals , Humans , Lectins, C-Type/metabolism , Lymphatic Metastasis , Mannose Receptor , Mannose-Binding Lectins/metabolism , Microscopy, Electron, Transmission , Oligopeptides/pharmacokinetics , Radiochemistry , Rats , Rats, Wistar , Receptors, Cell Surface/metabolism , Sentinel Lymph Node Biopsy , Spectrum Analysis , Sulfhydryl Compounds/chemistry
3.
Nucl Med Commun ; 31(10): 889-95, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20683364

ABSTRACT

UNLABELLED: Fever of unknown origin (FUO) represents a challenge to clinical medicine, and bacterial cultures have been considered the 'gold standard' in discriminating between fevers resulting from bacterial infection and sterile inflammations. In nuclear medicine, a synthetic radiolabeled antimicrobial peptide (Tc-UBI) is used to image the molecular localization of infectious microorganisms. OBJECTIVE: The aim of this research was to determine the absolute and relative frequencies of Tc-UBI, by molecular imaging, to detect infection foci in patients with fever in study or FUO. METHODS: Images (207) from 196 patients with FUO acquired with Tc-UBI and a Siemens gammacamera were read by two nuclear medicine physicians and classified as positive or negative for infection foci. The diagnostic value was corroborated with our gold standard, which comprises bacterial cultures of biopsies, blood and urine, plus laboratory studies, morphological images (radiographs, nuclear magnetic resonance, computed tomography) and the clinical history of each patient. The absolute and relative frequencies of Tc-UBI were calculated from the molecular images versus the gold standard. RESULTS: The specificity of Tc-UBI for localizing infection foci and for discarding sterile inflammation was 95.35%, the sensitivity was 97.52%, the positive predictive value was 96.72%, the negative predictive value was 96.47%, the accuracy was 96.62%, and the observed agreement between the bacterial culture and the molecular image was 96.62% (P=0.0001). CONCLUSION: Considering that the absolute and relative frequencies are very high, we propose that, in the future, Tc-UBI molecular imaging could be the gold standard to detect infection sites and to discard sterile inflammation.


Subject(s)
Bacterial Infections/complications , Bacterial Infections/diagnosis , Fever of Unknown Origin/complications , Organotechnetium Compounds , Peptide Fragments , Adolescent , Adult , Aged , Bacterial Infections/pathology , Biopsy , Diagnosis, Differential , Female , Humans , Inflammation/complications , Inflammation/diagnosis , Male , Middle Aged , Predictive Value of Tests , Sensitivity and Specificity
4.
J Pharm Pharmacol ; 62(4): 456-61, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20604834

ABSTRACT

OBJECTIVES: The radiopharmacokinetic parameters of the therapeutic radiopharmaceutical (188)Re-lanreotide were compared in rats implanted with hepatocarcinoma tumours (n= 18) and healthy rats (n= 18). METHODS: Rats were injected with approximately 1.8 MBq (188)Re-lanreotide (0.1 ml) via the tail vein and blood samples were obtained. The activity per gram of tissue (%IA/g) was calculated and the radiopharmacokinetic parameters determined. Data were fitted using a two-compartment model. KEY FINDINGS: Significant differences were found between healthy and hepatoma rats for beta elimination half-life (22.56 vs 48.14 h); transference constants K(10) (k(e)) (6.44 vs 3.05 h(-1)) and K(12) (2.76 vs 7.09 h(-1)); volume of distribution (2.06 vs 5.45 ml); mean residence time (66.58 vs 95.50 h) and apparent volume of distribution at steady state (131.30 vs 810.37 ml). The tumour/organ ratios after 24 h were 11.20 for tumour/muscle, 8.00 for tumour/liver and 7.72 for tumour/bone. The scintigraphic images obtained therefore had high resolution. CONCLUSIONS: (188)Re-lanreotide had a prolonged beta elimination half-life and increased volume of distribution in rats with hepatocellular carcinoma. This may be beneficial in the diagnosis and therapy of metastatic lesions in patients with cancer.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/metabolism , Peptides, Cyclic/pharmacokinetics , Radiopharmaceuticals/pharmacokinetics , Rhenium/pharmacokinetics , Somatostatin/analogs & derivatives , Animals , Antineoplastic Agents/therapeutic use , Bone and Bones , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/radiotherapy , Half-Life , Liver , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/drug therapy , Liver Neoplasms/radiotherapy , Male , Muscles , Peptides, Cyclic/therapeutic use , Radioisotopes/pharmacokinetics , Radioisotopes/therapeutic use , Radionuclide Imaging , Radiopharmaceuticals/therapeutic use , Rats , Rats, Wistar , Reference Values , Rhenium/therapeutic use , Somatostatin/pharmacokinetics , Somatostatin/therapeutic use , Tissue Distribution
5.
Bioconjug Chem ; 18(5): 1560-7, 2007.
Article in English | MEDLINE | ID: mdl-17665873

ABSTRACT

Two synthetic procedures for HYNIC oxytocin labeling were developed: one based on an orthogonal protection approach and the other with prelabeled (Boc)HYNIC-(Fmoc) amino acids. Both procedures were compared and applied to the preparation of several HYNIC-oxytocin derivatives where ligand position and amino acid (lysine and phenylalanine) were varied. Additionally, an oxytocin derivative labeled with HYNIC in the alpha-amino group of the Cys1 residue was also prepared. 99mTc-ethylendiaminediacetic acid (EDDA) labeling efficiencies were examined for all the derivatives, resulting in two candidates which showed affinity for the oxytocin receptor. Further biochemical experiments demonstrated that 99mTc-EDDA/HYNIC-Cys1-OT-CONH2 could be used as a potential radiopharmaceutical for breast cancer diagnosis.


Subject(s)
Breast Neoplasms/pathology , Hydrazines/chemical synthesis , Nicotinic Acids/chemical synthesis , Oxytocin/chemical synthesis , Radionuclide Imaging/methods , Radiopharmaceuticals , Amino Acids/chemistry , Animals , Edetic Acid/analogs & derivatives , Edetic Acid/chemistry , Fluorenes/chemistry , Humans , Lysine/chemistry , Membrane Proteins/chemistry , Mice , Organotechnetium Compounds/chemistry , Oxytocin/analogs & derivatives , Phenylalanine/chemistry , Somatostatin/analogs & derivatives , Somatostatin/chemistry , Staining and Labeling , Technetium Compounds/chemistry , Time Factors
6.
Rev Invest Clin ; 59(5): 373-81, 2007.
Article in Spanish | MEDLINE | ID: mdl-18268893

ABSTRACT

The 3 foundations of nuclear medicine are radiation conscious personnel, specific radiopharmaceuticals and equipment. The trend in molecular radiopharmacy is to develop new radiopharmaceuticals targeting peptides and receptors. 99mTc-radiopharmaceuticals give important clinical and molecular information especially in endocrinology, oncology and cardiology. The basic equipment has relied on crystal scintillation detector gamma cameras and the obtained images represent organ function provided by the specific radiopharmaceutical. Gamma cameras for single emission computed tomography (SPECT) can be added to an X-ray computed tomography (CT) equipment to form a hybrid (SPECT/ CT). The system is coupled to computer algorithms and special software to acquire and process the separate studies and fuse the two images to give a 3-D image of organ function plus anatomy. The new semiconductor or solid state detectors are a big improvement in commercial hybrid scintillation cameras and micro-SPECT/CT. Fused images obtained with SPECT/CT have been very useful in almost all medical areas and play an important role in preclinical research. The aim of this work is to present the current status and future trends of SPECT/CT systems in the clinical practice of nuclear medicine using technetium-99m radiopharmaceuticals. The development of molecular, functional and genetic imaging tools aided by new technology and SPECT/CT image fusion will enhance accurate diagnoses, and understanding of molecular mechanisms of disease and their respective response to radiopharmaceutical therapy.


Subject(s)
Neoplasms/diagnostic imaging , Radiopharmaceuticals , Technetium Compounds , Tomography, Emission-Computed, Single-Photon , Tomography, X-Ray Computed , Humans , Tomography, Emission-Computed, Single-Photon/instrumentation
7.
Int J Pharm ; 310(1-2): 125-30, 2006 Mar 09.
Article in English | MEDLINE | ID: mdl-16423478

ABSTRACT

Radiolabeled peptides, like the somatostatin analogs, have been used for peptide receptor-mediated radionuclide therapy (PRMRT) in metastatic neuroendocrine tumors. The eight amino acid peptide 3-(2-naphthalenyl)-D-alanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L-threoninamide,cyclic(2-->7)-disulfide (9Cl) (lanreotide) was found to bind to the five somatostatin tumor receptors. Lanreotide has been labeled via the bifunctional chelating agent, DOTA, to (111)In, and (90)Y. A direct labeling method was used to label lanreotide with (188)Re. Athymic mice with implanted human cancer tumors (uterine-cervix, renal, and neuroblastoma) were injected with radiochemically pure (188)Re-lanreotide (1.11 MBq). The percent injected activity (%IA/g) from serial blood samples was the input data for the WinNonlin computer program to obtain radiopharmacokinetic parameters. The organs' percent injected activity per gram of tissue (%IA/g) was extrapolated to the weights of a 70 kg male model organs and the number of nuclear transitions (N) were the input for the OLINDA/EXM program to obtain dosimetry estimates. Induced uterine-cervix tumors (HeLa cells) show a mean 2.4 %IA/g uptake up to 24 h and the tumor/blood ratio was over 1.85 (1.5-24 h post-injection) confirming (188)Re-lanreotide remains bound to the tumor. The estimated tumor absorbed dose was 460 mGy/MBq. Human effective dose was 0.0182 mSv/MBq. Therefore, (188)Re-lanreotide is a good candidate for PRMRT and a clinical trial is being planned in order to acquire individual dosimetric data.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Kidney Neoplasms/metabolism , Neuroblastoma/metabolism , Peptides, Cyclic/pharmacokinetics , Radioisotopes , Radiopharmaceuticals/pharmacokinetics , Rhenium , Somatostatin/analogs & derivatives , Uterine Cervical Neoplasms/metabolism , Animals , Antineoplastic Agents/administration & dosage , Female , HeLa Cells , Humans , Injections, Intravenous , Kidney Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Models, Animal , Neoplasm Transplantation , Neuroblastoma/pathology , Peptides, Cyclic/administration & dosage , Radiation Dosage , Radiopharmaceuticals/administration & dosage , Radiopharmaceuticals/chemical synthesis , Somatostatin/administration & dosage , Somatostatin/pharmacokinetics , Tissue Distribution , Uterine Cervical Neoplasms/pathology
8.
Appl Radiat Isot ; 61(6): 1261-8, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15388119

ABSTRACT

99mTc-UBI 29-41 is an antimicrobial peptide fragment that directly radiolabeled with 99mTc shows high in vitro and in vivo stability, rapid background clearance, minimal accumulation in non-target tissues and rapid detection of infection sites. Molecular mechanics (MM) calculation has been an essential tool in explaining experimental results associated with molecular recognition and stability. This work is an attempt to explain the 99mTc-UBI 29-41 specificity for bacteria and to understand from a structural point of view, the experimental results indicative of a molecular recognition and stability not well favored for two other cationic peptides (99mTc-Tat-1-Scr and 99mTc-Tat-2-Scr ) used as control. Structures of 99mTc-UBI, 99mTc-Tat-1-Scr, 99mTc-Tat-2-Scr and of the corresponding free cationic peptides were built and the optimized structures, in the best stable configurations, were calculated by a MM procedure. In order to correlate the calculated and experimental results, in vitro stability tests with cysteine challenge and stability to dilution in human serum and in saline solution, were performed for the three labeled cationic peptides. The three complexes can be represented by the general formula [Tc(V)(O)(H2O)2(Lysn=1,2-Argn=0,1-peptide)]10+,11+. The potential energies were 104.5, 95.6 and 90.8 kcal/mol for 99mTc-Tat-1-Scr, 99mTc-Tat-2-Scr and 99mTc-UBI 29-41, respectively. Experimental and calculated results were in good agreement. It is thus possible to predict and explain that in similar solution media 99mTc-Tat-2-Scr would be more stable than 99mTc-Tat-1-Scr and why 99mTc-UBI shows the highest stability. In conclusion, the in vitro specific binding to bacteria and the accumulation at infection sites in humans of 99mTc-labeled UBI could be the result of its high thermodynamic stability, selectivity and stereospecificity.


Subject(s)
Models, Molecular , Organotechnetium Compounds/blood , Organotechnetium Compounds/chemistry , Peptide Fragments/blood , Peptide Fragments/chemistry , Bacterial Infections/diagnostic imaging , Computer Simulation , Drug Stability , Humans , Protein Binding , Protein Conformation , Radionuclide Imaging , Radiopharmaceuticals/blood , Radiopharmaceuticals/chemistry , Structure-Activity Relationship
9.
Nucl Med Commun ; 25(6): 615-21, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15167523

ABSTRACT

BACKGROUND AND AIM: Bone-seeking radiopharmaceuticals have been proposed for delivering ablative radiation doses to marrow in multiple myeloma and other haematological malignancies. The aim of this research was to examine the feasibility of labelling ethylenediaminetetramethylenephosphonate (EDTMP) with Dy/Ho as an in vivo generator system and to evaluate whether the in vitro and in vivo stability of Dy-EDTMP and Ho-EDTMP complexes is maintained when the daughter Ho is formed. METHODS: Dy was obtained by neutron irradiation of enriched Dy2O3 in a TRIGA Mark III reactor. Labelling was carried out in an aqueous phosphate medium at pH 8.0 by addition of DyCl3 to EDTMP at a molar ratio 1:1.75. Dy/Ho labelled EDTMP was obtained with a 99.3+/-0.6% radiochemical purity determined by thin-layer chromatography and high-performance liquid chromatography. RESULTS: In vitro studies demonstrated that Dy/Ho-EDTMP is unstable after dilution in saline and stable in human serum and no translocation of the daughter nucleus occurring subsequent to beta decay of Dy which could produce release of Ho. Biodistribution in mice shows a fast blood clearance after administration of Dy/Ho-EDTMP with a skeletal uptake of 22.32+/-1.86% ID/g at 2 h and 20.12+/-1.94% ID/g after 10 d, a rapid renal elimination and no accumulation in other organs. Theoretical bone marrow absorbed dose calculations indicate that the Dy/Ho-EDTMP in vivo generator system would produce 7.80 times more radiation dose to marrow than that produced by Sm-EDTMP and 3.47 times more than Ho-DOTMP per unit of initial activity retained in the skeleton. CONCLUSION: The prepared radiolabelled EDTMP has adequate properties as a stable in vivo generator system for bone marrow ablation.


Subject(s)
Bone Marrow/metabolism , Isotope Labeling/methods , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacokinetics , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacokinetics , Animals , Bone Marrow Neoplasms/radiotherapy , Drug Stability , Feasibility Studies , Male , Metabolic Clearance Rate , Mice , Mice, Inbred BALB C , Organ Specificity , Organometallic Compounds/therapeutic use , Organophosphorus Compounds/therapeutic use , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/therapeutic use , Tissue Distribution
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