Development of a kit-like radiofluorinated biomolecule leading to a controlled self-assembly of 18F nanoparticles for a smart PET imaging application.

A kit-like 18F-fluorination method has been successfully applied to prepare an activatable probe 1 with good radiochemical yield and high specific activity. The probe has good in vitro stability and favorable cell membrane permeability. A controlled condensation reaction was initiated, and self-assembly into nanoparticles occurred when the probe was in a reducing environment. Positron emission tomography (PET) imaging of the biothiol level in living subjects was conveniently and precisely realized using this probe. The present study may provide a new platform for the development of "smart" PET tracers for tumor imaging.

Prostate cancer imaging of FSHR antagonist modified with a hydrophilic linker.

Follicle-stimulating hormone receptor (FSHR) is selectively expressed in endothelial cells of prostate cancer (PCa) and becomes a potential target for tumor diagnosis and therapy. (18)F-Al-NOTA-MAL-FSH1 is a promising PET imaging probe for targeting FSHR; however, the unfavorable abdominal backgrounds may hamper clinical translation. GGGRDN is a new hydrophilic linker, which can improve the imaging quality of radiolabeled peptides. In this study, GGGRDN-FSH1 (denoted as FSH2) was designed and conjugated with NOTA-MAL for (18)F-Al radiolabeling. NOTA-MAL-FSH2 was obtained with about 50% yield and labeled using (18)F-Al in a one-step method within 20 min with a yield of 41.46 ± 10.36% (non-decay-corrected). The radiochemical purity was more than 95% and the specific activity was more than 50 GBq/µmol. The in vitro stability studies were determined in PBS and human serum. (18)F-Al-NOTA-MAL-FSH2 remained stable in PBS and human serum. Balb/c nude mice bearing PC-3 human PCa were used for in vivo study. PC-3 tumors were clearly visualized with good contrast to background through microPET. ROI analysis showed the tumor uptake values were 2.68 ± 0.52 and 1.97 ± 0.61%ID/g at 30 and 60 min post injection (p.i.), respectively. Biodistribution studies showed that the accumulations of (18)F-Al-NOTA-MAL-FSH2 in liver and intestine were 0.47 ± 0.11 and 0.12 ± 0.03%ID/g respectively at 60 min p.i. FSHR-binding specificity was also demonstrated by reduced tumor uptake after coinjection of excessive unlabeled FSH2. In conclusion, (18)F-Al-NOTA-MAL-FSH2 was successfully prepared in a one-step method and showed better pharmacokinetics than (18) F-Al-NOTA-MAL-FSH1. Favorable preclinical study revealed that (18)F-Al-NOTA-MAL-FSH2 appears to be a promising candidate for FSHR-positive tumor imaging.

Synthesis and biological evaluation of novel platinum complexes of imidazolyl-containing bisphosphonates as potential anticancer agents.

Four novel platinum complexes, [Pt(en)]2ZL (1), [Pt(en)]2IPrBP (2), [Pt(en)]2MIBP (3) and [Pt(en)]2EIBP (4) [en = ethylenediamine; ZL = 1-hydroxy-3-(1H-imidazol-1-yl)ethane-1,1-diylbisphosphonic acid, commonly known as zoledronic acid; IPrBP = 1-hydroxy-3-(1H-imidazol-1-yl)propane-1,1-diylbisphosphonic acid; MIBP = 1-hydroxy-2-(2-methyl-1H-imidazol-1-yl)ethane-1,1-diylbisphosphonic acid; EIBP = 1-hydroxy-2-(2-ethyl-1H-imidazol-1-yl)ethane-1,1-diylbisphosphonic acid], were prepared and evaluated against five human cancer cell lines, including U2OS, A549, HCT116, MDA-MB-231 and HepG2. While exhibiting lower efficacy on the inhibition of cancer cell lines than cisplatin (CDDP), four complexes showed higher cytotoxicity than the corresponding ligands and relatively stronger cytotoxic effect on the hepatoma cell lines HepG2, and the complex 1 showed higher cytotoxicity than others on the whole. These complexes have better selectivity than the corresponding ligands in inhibiting hepatocarcinoma cells rather than normal liver cells, and the selective inhibitory effect of the complex 1 at the high concentration (100 µM) is better than that at the low concentration. Morphology studies exhibited typical characteristics of cell apoptosis and the cell cycle distribution analysis indicated that the complexes can inhibit cancer cells by inducing the cell cycle arrest at the G2/M phase, exhibiting a similar mechanism of action to CDDP. The binding interaction of complex with DNA has been explored by circular dichroism (CD) and UV-Vis absorption spectra, demonstrating these new complexes have moderate binding affinity for DNA.

Enzyme-Controlled Intracellular Self-Assembly of (18)F Nanoparticles for Enhanced MicroPET Imaging of Tumor.

Herein, we report the development of a new "smart" radioactive probe (i.e., 1) which can undergo furin-controlled condensation and self-assembly of radioactive nanoparticles (i.e., 1-NPs) in tumor cells and its application for enhanced microPET imaging of tumors in nude mice co-injected with its cold analog (i.e., 1-Cold). Furin-controlled condensation of 1-Cold and self-assembly of its nanoparticles (i.e., 1-Cold-NPs) in vitro were validated and characterized with HPLC, mass spectra, SEM, and TEM analyses. Cell uptake studies showed that both 1 and 1-Cold have good cell permeability. TEM images of 1-Cold-treated MDA-MB-468 cells directly uncovered that the intracellular 1-Cold-NPs were at/near the location of furin (i.e., Golgi bodies). MTT results indicated that 50 µM 1-Cold did not impose cytotoxicity to MDA-MB-468 cells up to 12 hours. MicroPET imaging of MDA-MB-468 tumor-bearing mice indicated that mice co-injected with 1 and 1-Cold showed higher uptake and longer attenuation of the radioactivity in tumors than those mice only injected with same dosage of 1. Tumor uptake ratios of 1 between these two groups of mice reached the maximum of 8.2 folds at 240 min post injection. Biodistribution study indicated that the uptake ratios of 1 in kidneys between these two groups continuously increased and reached 81.9 folds at 240 min post injection, suggesting the formation of radioactive NPs (i.e., 1-NPs) in MDA-MB-468 tumors of mice co-injected with 1 and 1-Cold. And the nanoparticles were slowly digested and secreted from the tumors, accumulating in the kidneys. Our ''smart'' probe (i.e., 1), together with the strategy of co-injection, might help researchers trace the biomarkers of interest within a longer time window.

Molecular structure, IR spectra, and chemical reactivity of cisplatin and transplatin: DFT studies, basis set effect and solvent effect.

Three different density functional theory (DFT) methods were employed to study the molecular structures of cis-diamminedichloroplatinum(II) (CDDP) and trans-diamminedichloroplatinum(II) (TDDP). The basis set effect on the structure was also investigated. By comparing the optimized structures with the experimental data, a relatively more accurate method was chosen for further study of the IR spectra and other properties as well as the solvent effect. Nineteen characteristic vibrational bands of the title compounds were assigned and compared with available experimental data. The number of characteristic peaks for the asymmetric stretching and deformation vibrations of N-H can serve as a judgment for the isomer between CDDP and TDDP. Significant solvent effect was observed on the molecular structures and IR spectra. The reduced density gradient analysis was performed to study the intramolecular interactions of CDDP and TDDP, and the nature of changes in the structures caused by the solvent was illustrated. Several descriptors determined from the energies of frontier molecular orbitals (HOMO and LUMO) were applied to describe the chemical reactivity of the title compounds. The molecular electrostatic potential (MESP) surfaces showed that the amino groups were the most favorable sites that nucleophilic reagents tend to attack, and CDDP was easier to be attacked by nucleophilic reagents than TDDP.

Preliminary evaluation of [18F]AlF-NOTA-MAL-Cys39-exendin-4 in insulinoma with PET.

BACKGROUND: High expression of glucagon-like peptide-1 receptor (GLP-1R) in insulinoma supplies a potential drug target for tumor imaging. Exendin-4 can specifically bind to GLP-1R as an agonist and its analogs are extensively used in receptor imaging studies. PURPOSE: A new GLP-1R imaging agent, [(18)F]AlF-NOTA-MAL-Cys(39)-exendin-4, was designed and prepared for insulinoma imaging. METHODS: Cys(39)-exendin-4 was conjugated with NOTA-MAL, then the compound was radiolabeled with [(18)F]AlF complex to obtained [(18)F]AlF-NOTA-MAL-Cys(39)-exendin-4. The tumor-targeting characters of the tracer were evaluated in INS-1 cells and BALB/c nude mice models. RESULTS: [(18)F]AlF-NOTA-MAL-Cys(39)-exendin-4 can be efficiently produced with a yield of 17.5 ± 3.2% (non-decay corrected) and radiochemical purity of >95%. The IC50 value of displacement [(18)F]AlF-NOTA-MAL-Cys(39)-exendin-4 with Cys(39)-exendin-4 was 13.52 ± 1.36 nM. PET images showed excellent tumor visualization with high uptake (9.15 ± 1.6%ID/g at 30 min and 7.74 ± 0.87%ID/g at 60 min). The tumor to muscle, pancreas and liver ratios were 63.25, 3.85 and 7.29 at 60 min after injection. GLP-1R binding specificity was demonstrated by co-injection with an excess of unlabeled Cys(39)-exendin-4 and the tumor uptake was found to be reduced significantly. CONCLUSION: [(18)F]AlF-NOTA-MAL-Cys(39)-exendin-4 shows favorable characteristics for insulinoma imaging and may be translated to clinical studies.

Synthesis, crystal structure and antitumor effect of a novel copper(II) complex bearing zoledronic acid derivative.

A great majority of Cu(II) complexes currently studied in the anticancer research field exert their antiproliferative activities through ligand exchange. In this work, we present the synthesis and structural characterization of two novel Cu(II) complexes, {[Cu3(ZL)2(H2O)6]·6H2O}n (1) (ZL = 1-hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyldiphosphonic acid) and [Cu(IPrDP)2]·3H2O (2) (IPrDP = 1-hydroxy-3-(1H-imidazol-1-yl)propane-1,1-diyldiphosphonic acid). Due to the insolubility of polymer 1 in common solvents, only the biological activities of complex 2 were investigated. The antitumor activity of complex 2 was evaluated against a panel of human cancer cell lines, including U2OS, A549, HCT116, MDA-MB-231 and HepG2. Complex 2 exhibited comparable cytotoxic effect to cisplatin (CDDP) against the human colon carcinoma cells HCT116, and superior selectivity for inhibiting human hepatocarcinoma cells rather than normal liver cells. The cell cycle distribution analysis indicates that complex 2 inhibits human carcinoma cells by inducing the cell cycle arrest at the G2/M phase, showing a similar mechanism of action to that of CDDP. The binding interaction of complex 2 with calf thymus DNA (CT-DNA) has been explored by UV-vis absorption and circular dichroism (CD), demonstrating complex 2 has a moderate binding affinity for DNA through intercalation.

Crystal structure of N-(2-hy-droxy-eth-yl)-5-nitro-isophthalamic acid monohydrate.

In the title compound, C10H10N2O6·H2O, the carb-oxy-lic acid group and the nitro group are essentially coplanar with the benzene ring [maximum deviation = 0.0264 (9) Å], while the amide group is oriented at a dihedral angle of 9.22 (5)° with respect to the benzene ring. In the crystal, classical O-H⋯O and N-H⋯O hydrogen bonds and weak C-H⋯O inter-actions link the organic mol-ecules and water mol-ecules of crystallization into a three-dimensional supra-molecular architecture.

Insulinoma imaging with glucagon-like peptide-1 receptor targeting probe (18)F-FBEM-Cys (39)-exendin-4.

PURPOSE: Glucagon-like peptide-1 receptor (GLP-1R) is a specific target for insulinomas imaging since it is overexpressed in the tumor. Exendin-4 exhibits high affinity for the GLP-1R. In this study, a novel (18)F-labeled exendin-4 analog, (18)F-FBEM-Cys(39)-exendin-4, was synthesized and its potentials for GLP-1R imaging were also evaluated. METHODS: (18)F-FBEM was synthesized by coupling (18)F-fluorobenzoic acid ((18)F-FBA) with N-(2-aminoethyl) maleimide, and the reaction conditions were optimized. Cys(39)-exendin-4 was then conjugated with (18)F-FBEM to obtain (18)F-FBEM-Cys(39)-exendin-4. The GLP-1R targeting potential and pharmacokinetic profile of the tracer were analyzed in INS-1 insulinoma and MDA-MB-435 breast tumor model, respectively. RESULTS: Under the optimal conditions, the yield of radiolabeled (18)F-FBEM was 49.1 ± 2.0 % (based on (18)F-FBA, non-decay corrected). The yield of (18)F-FBEM-Cys(39)-exendin-4 was 35.1 ± 2.6 % (based on the starting (18)F-FBEM, non-decay corrected). The radiochemical purity of (18)F-FBEM-Cys(39)-exendin-4 is >95 %, and the specific activity was at least 35 GBq/µmol. The GLP-1R-positive INS-1 insulinoma xenograft was clearly visible with good contrast to background, whereas GLP-1R-negative MDA-MB435 breast tumor was barely visible. Low levels of radioactivity were also detected at pancreas and lungs due to few GLP-1R expressions. GLP-1R binding specificity was demonstrated by reduced INS-1 tumor uptake of the tracer after coinjection with an excess of unlabeled Cys(39)-exendin-4 at 1 h postinjection. CONCLUSION: The thiol-reactive reagent, (18)F-FBEM, was prepared with high yield and successfully conjugated to Cys(39)-exendin-4. Favorable preclinical data showing specific and effective tumor targeting by (18)F-FBEM-Cys(39)-exendin-4 suggest that the tracer may be a potential probe for insulinomas imaging.

PET imaging of prostate tumors with 18F-Al-NOTA-MATBBN.

Overexpression of the gastrin-releasing peptide receptor (GRPR) in prostate cancer provides a promising target for detection the disease. MATBBN is a new bombesin analog originating from the GRPR antagonists with a hydrophilic linker. In this study NOTA-conjugated MATBBN was labeled by the Al(18)F method and the potential of (18)F-Al-NOTA-MATBBN for prostate tumor PET imaging was also evaluated. NOTA-MATBBN was radiolabeled with (18) F using Al(18)F complexes. Partition coefficient, in vitro stability and GRPR binding affinity were also determined. PET studies were performed with (18)F-Al-NOTA-MATBBN in PC-3 tumor-bearing mice. (18)F-Al-NOTA-MATBBN can be produced within 30 min with a decay-corrected yield of 62.5 ± 2.1% and a radiochemical purity of >98%. The logP octanol-water value for the Al(18)F-labeled BBN analog was -2.40 ± 0.07 and the radiotracer was stable in phosphate-buffered saline and human serum for 2 h. The IC50 values of displacement for the (18)F-Al-NOTA-MATBBN with MATBBN was 126.9 ± 2.75 nm. The PC-3 tumors were clearly visible with high contrast after injection of the labeled peptide. At 60 min post-injection, the tumor uptakes for (18)F-Al-NOTA-MATBBN and (18)F-FDG were 4.59 ± 0.43 and 1.98 ± 0.35% injected dose/g, and tumor to muscle uptake radios for two tracers were 6.77 ± 1.10 and 1.78 ± 0.32, respectively. Dynamic PET revealed that (18) F-Al-NOTA-MATBBN was excreted mainly through the kidneys. GRPR-binding specificity was also demonstrated by reduced tumor uptake of (18)F-Al-NOTA-MATBBN after coinjection with excess unlabeled MATBBN peptide at 1 h post-injection. NOTA- MATBBN could be labeled rapidly with (18)F using one step method. (18)F-Al-NOTA-MATBBN may be a promising PET imaging agent for prostate cancer.

A new (68)Ga-labeled BBN peptide with a hydrophilic linker for GRPR-targeted tumor imaging.

Bombesin (BBN) is a peptide exhibiting high affinity for the gastrin-releasing peptide receptor (GRPR), which is overexpressed on several types of cancers. Various GRPR antagonists and agonists have been labeled with radiometals for positron emission tomography (PET) imaging of GRPR-positive tumors. However, unfavorable hepatobiliary excretion such as high intestinal activity may prohibit their clinical utility for imaging abdominal cancer. In this study, the modified BBN peptide with a new hydrophilic linker was labeled with (68)Ga for PET imaging of GRPR-expressing PC-3 prostate cancer xenograft model. GRPR antagonists, MATBBN (Gly-Gly-Gly-Arg-Asp-Asn-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHCH2CH3) and ATBBN (D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHCH2CH3), were conjugated with 1,4,7-triazacyclononanetriacetic acid (NOTA) and labeled with (68)Ga. Partition coefficient and in vitro stability were also determined. GRPR binding affinity of both tracers was investigated by competitive radioligand binding assay. The in vivo receptor targeting potential and pharmacokinetic of (68)Ga-NOTA-MATBBN were also evaluated in PC-3 prostate tumor model and compared with those of (68)Ga-NOTA-ATBBN. NOTA-conjugated BBN analogs were labeled with (68)Ga within 20 min with a decay-corrected yield ranging from 90 to 95 % and a radiochemical purity of more than 98 %. The specific activity of (68)Ga-NOTA-MATBBN and (68)Ga-NOTA-ATBBN was at least 16.5 and 11.9 GBq/µmol, respectively. The radiotracers were stable in phosphate-buffered saline and human serum. (68)Ga-NOTA-MATBBN was more hydrophilic than (68)Ga-NOTA-ATBBN, as indicated by their log P values (-2.73 ± 0.02 vs. -1.20 ± 0.03). The IC50 values of NOTA-ATBBN and NOTA-MATBBN were similar (102.7 ± 1.18 and 124.6 ± 1.21 nM). The accumulation of (68)Ga-labeled GRPR antagonists in the subcutaneous PC-3 tumors could be visualized via small animal PET. The tumors were clearly visible, and the tumor uptakes of (68)Ga-NOTA-MATBBN and (68)Ga-NOTA-ATBBN were determined to be 4.19 ± 0.32, 4.00 ± 0.41, 2.93 ± 0.35 and 4.70 ± 0.40, 4.10 ± 0.30, 3.14 ± 0.30 %ID/g at 30, 60, and 120 min, respectively. There was considerable accumulation and retention of (68)Ga-NOTA-ATBBN in the liver and intestines. In contrast, the abdominal area does not have much retention of (68)Ga-NOTA-MATBBN. Biodistribution data were in accordance with the PET results, showing that (68)Ga-NOTA-MATBBN had more favorable pharmacokinetics and higher tumor to background ratios than those of (68)Ga-NOTA-ATBBN. At 1 h postinjection, the tumor to liver and intestine of (68)Ga-NOTA-MATBBN were 8.05 ± 0.56 and 21.72 ± 3.47 and the corresponding values of unmodified counterpart were 0.85 ± 0.23 and 3.45 ± 0.43, respectively. GRPR binding specificity was demonstrated by reduced tumor uptake of radiolabeled tracers after coinjection of an excess of unlabeled BBN peptides. (68)Ga-NOTA-MATBBN exhibited GRPR-targeting properties both in vitro and in vivo. The favorable characterizations of (68)Ga-NOTA-MATBBN such as convenient synthesis, specific GRPR targeting, high tumor uptake, and satisfactory pharmacokinetics warrant its further investigation for clinical cancer imaging.

Pilot study of a novel (18)F-labeled FSHR probe for tumor imaging.

PURPOSE: Follicle-stimulating hormone receptor (FSHR) is overexpressed in primary and metastatic tumor. Molecular imaging of FSHR is beneficial for prognosis and therapy of cancer. FSHß(33-53) (YTRDLVYKDPARPKIQKTCTF), denoted as FSH1, is a FSHR antagonist. In the present study, maleimide-NOTA conjugate of FSH1 (NOTA-MAL-FSH1) was designed and labeled with [(18)F] aluminum fluoride. The resulting tracer, (18)F-Al-NOTA-MAL-FSH1, was preliminarily evaluated in PET imaging of FSHR-positive tumor. PROCEDURES: NOTA-MAL-FSH1 was synthesized and radiolabeled with Al(18)F complex. The tumor-targeting potential and pharmacokinetic profile of the (18)F-labeled compound were evaluated in vitro and in vivo using a PC3 human prostate tumor model. RESULTS: (18)F-Al-NOTA-MAL-FSH1 can be efficiently produced within 30 min with a non-decay-corrected yield of 48.6 ± 2.1 % and a radiochemical purity of more than 95 %. The specific activity was at least 30 GBq/µmol. The radiotracer was stable in phosphate-buffered saline and human serum for at least 2 h. The IC50 values of displacement (18)F-Al-NOTA-MAL-FSH1 with FSH1 were 252 ± 1.12 nM. The PC3 human prostate tumor xenografts were clearly visible with high contrast after injection of (18)F-Al-NOTA-MAL-FSH1 via microPET. At 30, 60 and 120 min postinjection, the tumor uptakes were 2.98 ± 0.29 % injected dose (ID)/g, 2.53 ± 0.20 %ID/g and 1.36 ± 0.12 %ID/g, respectively. Dynamic PET scanning showed that tumor uptake reached a plateau by about 6 min. Heart peaked earlier and then cleared quickly. Biodistribution studies confirmed that the normal organs except kidney uptakes were all below 1 %ID/g at 1 h p.i. The tumor-to-blood and tumor-to-muscle ratio at 10 min, 0.5, 1, and 2 h after injection were 1.64 ± 0.36, 2.97 ± 0.40, 9.31 ± 1.06, and 13.59 ± 2.33 and 7.05 ± 1.10, 10.10 ± 1.48, 16.17 ± 3.29, and 30.88 ± 4.67, respectively. The tracer was excreted mainly through the renal system, as evidenced by high levels of radioactivity in the kidneys. FSHR-binding specificity was also demonstrated by reduced tumor uptake of (18)F-Al-NOTA-MAL-FSH1 after coinjection with an excess of unlabeled FSH1 peptide. CONCLUSION: NOTA-MAL-FSH1 could be labeled rapidly and efficiently with (18)F using one step method. Favorable preclinical data suggest that (18)F-Al-NOTA-MAL-FSH1 may be a suitable radiotracer for the non-invasive visualization of FSHR positive tumor in vivo.

Synthesis and pharmacological evaluation of 99mTc-labeled imidazolyl-containing diphosphonic acid as a novel bone imaging agent.

In order to develop a superior bone imaging agent, a new radiotracer (99m)Tc-1-hydroxy-5-(2-butyl-1H-imidazol-1-yl)pentane-1,1-diyldiphosphonic acid (BIPeDP) was designed and prepared with good radiochemical yield and stability. The biodistribution in mice shows that (99m)Tc-BIPeDP has high specificity in the skeleton with the maximum uptake of 17.30 ± 0.14 injected dose per gram at 60 min. Kinetics of blood clearance shows that the distribution half-life (T1/2α) and elimination half-life (T1/2ß) of (99m)Tc-BIPeDP are 3.7 and 49.7 min, respectively. An excellent image can be obtained at 1-h post-injection with the single photon emission computed tomography bone scanning, which is clearer and quicker than (99m)Tc-zoledronic acid, (99m)Tc-1-hydroxy-5-(1H-imidazol-1-yl)pentane-1,1-diyldiphosphonic acid, and (99m)Tc-methylenediphosphonic acid All results indicate that (99m)Tc-BIPeDP holds great potential as a novel promising bone imaging agent.

First experience of 18F-alfatide in lung cancer patients using a new lyophilized kit for rapid radiofluorination.

UNLABELLED: (18)F-FPPRGD2, which was approved for clinical study recently, has favorable properties for integrin targeting and showed potential for antiangiogenic therapy and early response monitoring. However, the time-consuming multiple-step synthesis may limit its widespread applications in the clinic. In this study, we developed a simple lyophilized kit for labeling PRGD2 peptide ((18)F-AlF-NOTA-PRGD2, denoted as (18)F-alfatide) using a fluoride-aluminum complex that significantly simplified the labeling procedure. METHODS: Nine patients with a primary diagnosis of lung cancer were examined by both static and dynamic PET imaging with (18)F-alfatide, and 1 tuberculosis patient was investigated using both (18)F-alfatide and (18)F-FDG imaging. Standardized uptake values were measured in tumors and other main organs at 30 min and 1 h after injection. Kinetic parameters were calculated by Logan graphical analysis. Immunohistochemistry and staining intensity quantification were performed to confirm the expression of integrin α(v)ß(3). RESULTS: Under the optimal conditions, the whole radiosynthesis including purification was accomplished within 20 min with a decay-corrected yield of 42.1% ± 2.0% and radiochemical purity of more than 95%. (18)F-alfatide PET imaging identified all tumors, with mean standardized uptake values of 2.90 ± 0.10. Tumor-to-muscle and tumor-to-blood ratios were 5.87 ± 2.02 and 2.71 ± 0.92, respectively. CONCLUSION: (18)F-alfatide can be produced with excellent radiochemical yield and purity via a simple, 1-step, lyophilized kit. PET scanning with (18)F-alfatide allows specific imaging of αvß3 expression with good contrast in lung cancer patients. This technique might be used for the assessment of angiogenesis and for planning and response evaluation of cancer therapies that would affect angiogenesis status and integrin expression levels.

A novel (99m)Tc-labeled diphosphonic acid as potential bone seeking agent: synthesis and biological evaluation.

A novel zoledronate derivative, 1-hydroxy-4-(2-butyl-1H-imidazol-1-yl)butane-1,1- diyldiphosphonic acid (BIBDP) was prepared and labeled with (99m)Tc successfully in a high radiochemical purity and good stability in vitro. The biodistribution in mice shows that (99m)Tc-BIBDP has high specificity and efficacy in bone uptake with a maximum of 12.14 ± 0.53 %ID/g at 120 min. Kinetics of blood clearance showed that distribution half life (T(1/2α)), elimination half life (T(1/2ß)) and total clearance rate (CL) of (99m)Tc-BIBDP were 4.67 min, 91.9 min and 1.21 %ID/g·min(-1), respectively. Moreover, (99m)Tc-BIBDP has higher uptake in the bone and faster clearance from soft tissues than (99m)Tc-MDP and (99m)Tc-ZL. A plain and clear bone image was obtained at 1 h with SPECT bone imaging. The present findings indicate that (99m)Tc- BIBDP holds great potential for bone imaging.

3,4,6-Tri-O-acetyl-1,2-O-[1-(exo-ethoxy)ethylidene]-ß-D-mannopyranose 0.11-hydrate.

The title compound, C(16)H(24)O(10)·0.11H(2)O, is a key intermediate in the synthesis of 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG), which is the most widely used molecular-imaging probe for positron emission tomography (PET). The crystal structure has two independent molecules (A and B) in the asymmetric unit, with closely comparable geometries. The pyranose ring adopts a (4)C(1) conformation [Cremer-Pople puckering parameters: Q = 0.553 (2) Å, θ = 16.2 (2)° and φ = 290.4 (8)° for molecule A, and Q = 0.529 (2) Å, θ =15.3 (3)° and φ = 268.2 (9)° for molecule B], and the dioxolane ring adopts an envelope conformation. The chiral centre in the dioxolane ring, introduced during the synthesis of the compound, has an R configuration, with the ethoxy group exo to the mannopyranose ring. The asymmetric unit also contains one water molecule with a refined site-occupancy factor of 0.222 (8), which bridges between molecules A and B via O-H···O hydrogen bonds.

Development of superior bone scintigraphic agent from a series of (99m)Tc-labeled zoledronic acid derivatives.

Two novel zoledronic acid (ZL) derivatives, 1-hydroxy-4-(1H-imidazol-1-yl)butane-1,1-diyldiphosphonic acid (IBDP) and 1-hydroxy-5-(1H-imidazol-1-yl)pentane-1,1-diyldiphosphonic acid (IPeDP), were prepared and labeled with the radionuclide technetium-99m in a high labeling yield. In vitro stabilities of these radiolabeled complexes were measured by the radio-HPLC analysis as a function of time, which showed excellent stability with the radiochemical purity of over 95% at 6h post preparation. Their in vivo biological performances were evaluated and compared with those of (99m)Tc-ZL and (99m)Tc-MDP (methylenediphosphonic acid). The biodistribution in mice and scintigraphic images of the rabbit showed that the tracer agent (99m)Tc-IPeDP had highly selective uptake in the skeletal system and rapid clearance from the blood and soft tissues and an excellent scintigraphic image can be obtained in a shorter time post injection with clear visualization of the skeleton and low soft tissue activity. These preclinical studies suggest that (99m)Tc-IPeDP would be a novel superior bone scintigraphic agent.

Preparation and in vivo biological investigations on a novel radioligand for bone scanning: technetium-99m-labeled zoledronic acid derivative.

INTRODUCTION: To enable imaging at an earlier time after injection, a radiopharmaceutical with higher affinity for bone, larger ratio of bone-to-soft tissue uptake and more rapid clearance from blood is required. The nature of diphosphonic acid is a key factor to determine the advantages of the radiopharmaceuticals. The purpose of this study is to optimize the linker chain between the imidazolyl and geminal diphosphonate group in the zoledronic acid (ZL) to develop novel single photon emission computed tomography (SPECT) bone imaging agent. METHODS: A novel ZL derivative, 1-hydroxy-3-(1H-imidazol-1-yl)propane-1,1-diyldiphosphonic acid (IPrDP), was successfully prepared and labeled with (99m)Tc in a high labeling yield. Biodistribution of (99m)Tc-IPrDP and (99m)Tc-ZL in normal mice were studied and compared. SPECT bone scanning was performed on the rabbit and a series of dynamic and static images were recorded by Philips SKY Light emission computed tomography. RESULTS: In the biodistribution studies, (99m)Tc-IPrDP exhibits significant advantages on the bone resorption and the clearance from soft tissues compared with (99m)Tc-ZL. Kinetics of blood clearance in mice showed that T(1/2α) and T(1/2ß) of (99m)Tc-IPrDP were 1.47 min and 46.47 min, while those of (99m)Tc-ZL were 2.28 and 52.63 min respectively. Excellent images of the rabbit skeleton can be quickly obtained for (99m)Tc-IPrDP, which was faster than (99m)Tc-ZL and the clinically widely used bone imaging agent (99m)Tc-MDP (technetium-99m labeled with methylenediphosphonate). CONCLUSIONS: (99m)Tc-IPrDP possesses excellent characteristics for the potential application as a novel bone scanning agent.

Synthesis and biological evaluation of novel (99m)Tc-labelled bisphosphonates as superior bone imaging agents.

A series of novel zoledronic acid (ZL) derivatives 1-hydroxy-3-(2-methyl-1H-imidazol-1-yl)propane-1,1-diyldiphosphonic acid (MIPrDP), 1-hydroxy-4-(2-methyl-1H-imidazol-1-yl)butane-1,1-diyldiphosphonic acid (MIBDP), and 1-hydroxy-5-(2-methyl-1H-imidazol-1-yl)pentane-1,1-diyldiphosphonic acid (MIPeDP) were prepared and successfully labeled with (99m)Tc in high labeling yields. The in vitro stability and in vivo biodistribution of (99m)Tc-MIPrDP, (99m)Tc-MIBDP and (99m)Tc-MIPeDP were investigated and compared. The biodistribution studies indicate that the radiotracer (99m)Tc-MIPrDP has highly selective uptake in the skeletal system and rapid clearance from soft tissues. The present findings indicate that (99m)Tc-MIPrDP holds great potential for use in bone imaging.

Animal studies of 99mTc-i-PIDP: a new bone imaging agent.

This study was to investigate the preparation and biodistribution of (99m)Tc-labeled novel zoledronic acid derivative 1-hydroxy-2-(2-isopropyl-1H-imidazole-1-yl) ethylidene-1,1-bisphosphonic ((99m)Tc-i-PIDP) as a potential bone imaging agent. Satisfactory labeling results (radiochemical purity over 95%) were obtained when the amount of i-PIDP, Na(99m)TcO(4), and SnCl(2)·2H(2)O, were 5 mg, 37 MBq, and 100 µg, respectively, the pH value was between 4.0 and 6.0, and the labeling reaction continued for 30 min. The labeled complex was stable at least up to 6h in vitro. The biodistribution and pharmacokinetics studies in mice and single photon emission computed tomography (SPECT) bone scan in rabbit of (99m)Tc-i-PIDP were systematically studied. The results showed that the bone uptake is up to 9.63%ID/g at 60 min after injection of (99m)Tc-i-PIDP. The pharmacokinetic studies indicate that the data can be fitted to a two-compartment model with the equation of C=5.80e(-0.20t)+2.66e(-0.01t). A plain bone image was obtained at 1 h. All of the results suggested that (99m)Tc-i-PIDP is worthy of future investigation as a novel bone imaging agent.