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BACKGROUND: There is a need to develop new and more potent radiofluorinated peptide and their hybrid conjugates for multiple-receptors targeting properties that overexpress on many cancers. METHODS: We have synthesized MUC1-[18F] SFB and MUC1-FA-[18F] SFB hybrid conjugates using a convenient and one-step nucleophilic displacement reaction. In vitro cell binding and in vivo evaluation in animals were performed to determine the potential of these radiolabeled compounds. RESULTS: Radiochemical yields for MUC1-[18F] SFB and MUC1-FA-[18F] SFB conjugates were greater than 70% in less than 30 min synthesis time. Radiochemical purities were greater than 97% without HPLC purification, which makes these approaches amenable to automation. In vitro studies on MCF7 breast cancer cells showed that the significant amounts of the radiofluorinated conjugates were associated with cell fractions and held good affinity and specificity for MCF7 cells. In vivo characterization in Balb/c mice revealed rapid blood clearance with excretion predominantly by urinary as well as hepatobiliary systems for MUC1-[18F] SFB and MUC1-FA-[18F] SFB, respectively. Biodistribution in SCID mice bearing MCF7 xenografts, demonstrated excellent tumor uptake (12% ID/g) and favorable kinetics for MUC1-FA-[18F] SFB over MUC1-[18F]SFB. The tumor uptake was blocked by the excess co-injection of cold peptides suggesting the receptor-mediated process. CONCLUSION: Initial PET/CT imaging of SCID mice with MCF7 xenografts, confirmed these observations. These results demonstrate that MUC1-FA-[18F] SFB may be a useful PET imaging probe for breast cancer detection and monitoring tumor response to the treatment.

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Myocardial perfusion imaging (MPI) is one of the most commonly performed investigations in nuclear medicine studies. Due to the physical properties of the positron emitter gallium-68 (68Ga) and its availability from 68Ge/68Ga generator, together with the well-known coordination chemistry, we have synthesized 68Ga-NOTA- and 68Ga-NODAGA-rhodamine conjugates using a straightforward and a one-step simple reaction. Radiochemical yields were greater than 95% (decay corrected), with total synthesis time of less than 30 min. Radiochemical purities were always greater than 98% as assessed by TLC and HPLC. These synthetic approaches hold considerable promise as simple method for 68Ga-rhodamine conjugates preparation, with high radiochemical yield and purity. Biodistribution studies in normal Fischer rats at 60 min post-injection, demonstrated significant (~3% ID/g) uptake and favorable biodistribution profile for 68Ga-NOTA-rhodamine over 68Ga-NODAGA-rhodamine conjugate. These results demonstrate that 68Ga-NOTA-rhodamine conjugate may be useful as probe for the PET evaluation of myocardial perfusion.

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A fully automated system was developed to produce rubidium-81 (81Rb), based on the natKr (p, n) 81Rb reaction. The energy incident on the target was 26MeV. Only 6MeV was stopped inside the gas and the remainder was stopped by a specially designed flange. The target body was characterized by its conical shape and its inner walls were chemically plated with 100±10µm of nickel (Ni). Ni is advantageous as a fairly good conductor of heat whose surface can resist solutions. Additionally, the Ni plated target allowed potassium chloride to dissolve 81Rb, with no further effect on the target body. The system produced 81Rb with a production yield of approximately 4.5mCi/µAh, which is close to the calculated expected yield of 5.3mCi/µAh. The system is able to deliver reliable and reproducible radioactivity for patients and can be operated up to 1500µAh before preventive maintenance is due. Key steps in designing the 81Rb target for selected energy ranges are reported here.

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In an attempt to develop a new and rapid method for labeling peptides with (18)F, we have synthesized MUC1-[(18)F]SFB and BBN-[(18)F]SFB peptide conjugates using a convenient and one-step simple reactions. Radiochemical yields for MUC1-[(18)F]SFB and BBN-[(18)F]SFB peptide conjugates were greater than 70% in less than 30 min synthesis time, thus amenable for automation for the radiofluorination of peptides. in vitro tests on T47D breast cancer cells showed that the significant amounts of the radioconjugates were associated with cell fractions and held sufficient affinities and specificities toward T47D cell line. These radioconjugates may be useful as molecular probes for detecting and staging of breast cancer and monitoring tumor response to treatment.

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In an attempt to develop new folate radiotracers with favorable biochemical properties for detecting folate receptor-positive cancers, we have synthesized [(124)I]-SIB- and [(124)I]-SIP-folate conjugates using a straightforward and two-step simple reactions. Radiochemical yields for [(124)I]-SIB- and [(124)I]-SIP-folate conjugates were greater than 90 and 60% respectively, with total synthesis time of 30-40min. Radiochemical purities were always greater than 98% without HPLC purification. These synthetic approaches hold considerable promise as rapid and simple method for (124)I-folate conjugate preparation with high radiochemical yield in short synthesis time. In vitro tests on KB cell line showed that the significant amounts of the radioconjugates were associated with cell fractions. In vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates and favorable biodistribution profile for [(124)I]-SIP-folate conjugate over [(124)I]-SIB-folate conjugate. Biodistribution studies of [(124)I]-SIP-folate conjugate in nude mice bearing human KB cell line xenografts, demonstrated significant tumor uptake. The uptake in the tumors was blocked by excess injection of folic acid, suggesting a receptor-mediated process. These results demonstrate that [(124)I]-SIP-folate conjugate may be useful as a molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis as well as monitoring tumor response to treatment.

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Human cancer cells overexpress many peptide receptors as molecular targets. Radiolabeled peptides that bind with high affinity and specificity to the receptors on tumor cells hold great potential for both diagnostic imaging and targeted radionuclide therapy. The advantage of solid-phase peptide synthesis, the availability of different chelating agents and prosthetic groups and bioconjugation techniques permit the facile preparation of a wide variety of peptide-based targeting molecules with diverse biological and tumor targeting properties. Some of these peptides, including somatostatin, bombesin, vasoactive intestinal peptide, gastrin, neurotensin, exendin and RGD are currently under investigation. It is anticipated that in the near future many of these peptides may find applications in nuclear oncology. This article presents recent developments in the field of small peptides, and their applications in the diagnosis and treatment of cancer.

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There is a need to develop more potent radiofluorinated folic acid conjugates for a better visualization of folate receptors that overexpress on many human cancers. Due to the clinical importance of [(18)F]-fluoro-2-deoxy-d-glucose ([(18)F]-FDG) and its availability in almost every positron-emission tomography center, new radiofluorinated [(18)F]-FDG-folate and methotrexate conjugates ([(18)F]-5 and [(18)F]-8) were synthesized using [(18)F]-FDG as a prosthetic group. In a convenient and simple one-step radiosynthesis, [(18)F]-5 and [(18)F]-8 conjugates were prepared in high radiochemical yields (>80%) with total synthesis time of almost 20 min, and radiochemical purities were found to be greater than 98% without high-performance liquid chromatography purification, which make these approaches amenable for automation. In vitro tests on KB cell line showed that a significant amount of the radioconjugates were associated with the cell fractions. In vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates with excretion predominantly by the urinary and hepatobiliary systems for [(18)F]-5 and [(18)F]-8 conjugates, respectively. Biodistribution studies in nude mice-bearing human KB cell line xenografts demonstrated significant tumor uptake and favorable kinetics profile for [(18)F]-5 over the other conjugate. The uptake in the tumors was blocked by the excess coinjection of cold folic acid, suggesting the receptor-mediated process. These results demonstrate that [(18)F]-5 may be useful as a molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis, as well as monitoring tumor response to the treatment.

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In an attempt to visualize folate receptors that overexpress on many cancers, [(18)F]-fluorobenzene and pyridinecarbohydrazide-folate/methotrexate conjugates ([(18)F]-1, [(18)F]-2-folates and [(18)F]-8, [(18)F]-9-MTXs) were synthesized by the nucleophilic displacement reactions using ethyl-trimethylammonium-benzoate and pyridinecarboxylate precursors. The intermediates ethyl [(18)F]-fluorinated benzene and pyridine esters were reacted with hydrazine to produce the [(18)F]-fluorobenzene and pyridinecarbohydrazides, followed by coupling with N-hydroxysuccinimide-folate/MTX. Radiochemical yields were greater than 80% (decay corrected), with total synthesis time of less than 45 min. Radiochemical purities were always greater than 97% without high-performance liquid chromatography purification. These synthetic approaches hold considerable promise as rapid and simple method for the radiofluorination of folate derivatives with high radiochemical yield in short synthesis time. In vitro tests on KB cell line showed that significant amount of the radioconjugates were associated with cell fractions, and in vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates with excretion predominantly by the urinary and partially by the hepatobiliary systems. Biodistribution studies in nude mice bearing human KB cell line xenografts demonstrated significant tumor uptake and favorable biodistribution profile for [(18)F]-2-folate over the other conjugates. The uptake in the tumors was blocked by excess coinjection of folic acid, suggesting a receptor-mediated process. Micro-positron emission tomography images of nude mice bearing human KB cell line xenografts confirmed these observations. These results demonstrate that [(18)F]-2-folate may be useful as molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis as well as monitoring tumor response to treatment.

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A hope for the diagnosis and treatment of cancer is the development of new tumor-specific peptide-based radiopharmaceuticals. The overexpression of many peptide receptors on human tumors makes such receptors an attractive potential target for diagnostic imaging and radiotherapy with specifically designed radiolabeled peptides. The use of solid-phase peptide synthesis, and the availability of a wide range of bifunctional chelating agents for the convenient radiolabeling of bioactive peptides with different radionuclides have produced a wide variety of medicinally useful peptide radiopharmaceuticals. A few of these peptides, such as somatostatin, bombesin, cholecystokinin/gastrin, neurotensin and vasoactive intestinal peptide are currently under investigation for their possible clinical applications in nuclear oncology. This article presents the recent development in radiolabeled small peptides, with major emphasis on somatostatin and bombesin analogs.

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In an effort to develop a peptide-based radiopharmaceutical for the detection of breast cancer, we have prepared an analog of alphaM2 peptide, modified to incorporate an N3S chelate system. Mercaptoacetyltriglycine (MAG)(3)-derivatized alphaM2 peptide was prepared by solid-phase synthesis and radiolabeled with (99m)Tc by an exchange method. In vitro cell-binding on human breast cancer cell lines, MDA-MB-231 and MCF-7, indicated the affinity and specificity of (99m)Tc-MAG(3)-alphaM2 toward breast cancer cells. Additionally, the radiolabeled peptide showed rapid internalization into human breast cancer cells. In vivo biodistribution in mice showed that the radiolabeled peptide cleared rapidly from the blood and most non-target tissues and was excreted significantly via the kidneys. Uptake of (99m)Tc-MAG(3)-alphaM2 in the tumor was moderate. The radiochemical and in vitro and in vivo characterization indicates that the radiolabeled peptide has certain favorable properties and it might be a useful radiopharmaceutical for the detection of breast cancer in vivo.

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BACKGROUND: Several human cancers, including small cell lung, prostate, breast, gastric, colon and pancreatic cancers, express receptors for bombesin-like peptides. Bombesin (BN) peptides that bind specifically to these receptors are useful for detection of bombesin receptor-expressing cancers in vivo. A new 99mTc-labelled-BN peptide for targeting bombesin receptor-expressing cancers was prepared and characterized. MATERIALS AND METHODS: MAG3-coupled BN peptide (MAG3-BN) was prepared by solid-phase synthesis and radiolabelled with 99mTc by an exchange method. In vitro cell binding assays were conducted on human breast cancer cell lines, MDA-MB-231 and MCF-7. In vivo biodistribution studies were performed in normal and nude mice bearing bombesin receptor-positive tumors. RESULTS: Radiolabelling of MAG3-BN with 99mTc produces a single radioactive species (> 95%). In vitro cell-binding indicated the affinity and specificity of 99mTc-MAG3-BN towards bombesin receptors. In vivo biodistribution in mice demonstrated that 99mTc-MAG3-BN cleared rapidly from the blood and most non-targeted tissues and was excreted mainly via the kidneys. Uptake in bombesin receptor-positive tissues and in the tumor was low to moderate. CONCLUSION: 99mTc-MAG3-BN displays good radiolabelling together with certain favorable biological characteristics and might be a useful peptide radiopharmaceutical in the detection of bombesin receptor-expressing cancers in vivo.

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The application of biologically active peptides labelled with positron-emitting nuclides has emerged as a useful and interesting field in nuclear medicine. Small synthetic receptor-binding peptides are currently the preferred agents over proteins and antibodies for diagnostic imaging of various tumours. Due to the smaller size of peptides, both higher target-to-background ratios and rapid blood clearance can often be achieved with radiolabelled peptides. Hence, short-lived positron emission tomography (PET) isotopes are potential candidates for labelling peptides. Among a number of positron-emitting nuclides, fluorine-18 appears to be the best candidate for labelling bioactive peptides by virtue of its favourable physical and nuclear characteristics. The major disadvantage of labelling peptides with 18F is the laborious and time-consuming preparation of the 18F labelling agents. In recent years, various techniques have been developed which allow efficient labelling of peptides with 18F without affecting their receptor-binding properties. Moreover, the development of a variety of prosthetic groups has facilitated the efficient and site-specific labelling of peptides with 18F. The 18F-labelled peptides hold enormous clinical potential owing to their ability to quantitatively detect and characterise a wide variety of human diseases when using PET. Recently, a number of 18F-labelled bioactive peptides have shown great promise as diagnostic imaging agents. This review presents the recent developments in 18F-labelled biologically active peptides used in PET.

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Nature has designed peptides to stimulate, inhibit or regulate many body functions. The development of radiolabelled peptide-based radiopharmaceuticals for imaging a variety of tumours, infection/inflammation and thrombus has seen a new era in nuclear medicine. Recently, a number of 99Tcm-labelled bioactive peptides have proven to be useful diagnostic imaging agents. Due to their small size, peptide molecules exhibit favourable pharmacokinetic characteristics, such as rapid uptake by target tissue and rapid blood clearance, which potentially allows images to be acquired earlier following the administration of a 99Tcm-labelled peptide radiopharmaceutical. The challenge is to label bioactive peptides with 99Tcm with high specific activity without impairing the biological properties of the peptides. Molecular engineering techniques now permit synthesis of a wide range of biologically active peptides that carry chelating groups in their structure without affecting their receptor binding properties, thus permitting a high specific activity product. This review presents recent developments in 99Tcm-labelled small peptides and their potential applications in the imaging of various types of diseases. In addition, the different techniques for radiolabelling small bioactive peptides, the pharmacokinetic properties of peptides, and their potential as diagnostic imaging agents are also addressed.

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