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Peptides are attracting increasing interest in nuclear oncology for targeted tumor diagnosis and therapy. We therefore synthesized new cyclic octapeptides conjugated with HYNIC by Fmoc solid-phase peptide synthesis. These were purified and analyzed by RP-HPLC, MALDI mass, (1)H NMR, (13)C NMR, HSQC, HMBC, COSY and IR spectroscopy. Conformational analysis of the peptides was performed by circular dichroism spectroscopy, in pure water and trifluoroethanol-water (1:1), revealed the presence of strong secondary structural features like β-sheet and random coils. Labeling was performed with (99m)Tc using Tricine and EDDA as coligands by SnCl(2) method to get products with excellent radiochemical purity >99.5 %. Metabolic stability analysis did not show any evidence of breaking of the labeled compounds and formation of free (99m)Tc. Internalization studies were done and IC(50) values were determined in somatostatin receptor-expressing C6 glioma cell line and rat brain cortex membrane, and the results compared with HYNIC-TOC as standard. The IC(50) values of (99m)Tc-HYNIC-His(3)-Octreotate (21 ± 0.93 nM) and (99m)Tc-HYNIC-TOC (2.87 ± 0.41 nM) proved to be comparable. Biodistribution and image study on normal rat under gamma camera showed very high uptake in kidney and urine, indicating kidney as primary organ for metabolism and route of excretion. Biodistribution and image study on rats bearing C6 glioma tumor found high uptake in tumor (1.27 ± 0.15) and pancreas (1.71 ± 0.03). Using these findings, new derivatives can be prepared to develop (99m)Tc radiopharmaceuticals for imaging somatostatin receptor-positive tumors.

The aim of this study was to develop (99m)Tc(CO)(3)-labeled fluoroquinolones as novel SPECT radiopharmaceuticals for imaging bacterial infection. Fluoroquinolones, e.g., ofloxacin (OFX), levofloxacin (LVX), lomefloxacin (LMX) and norfloxacin (NFX) were labeled with a fac-[(99m)Tc(CO)(3)(H(2)O)(3)](+) precursor. The radiochemical purity of the radiopharmaceuticals exceeded 97% as determined by thin layer chromatography and HPLC. No further purification was necessary before injection. The Re(CO)(3) complex of one of the fluoroquinolones (levofloxacin) was synthesized using [Re(CO)(3)(H(2)O)(3)]OTf and Re(CO)(5)Br precursors in separate experiments and characterized by IR, NMR and mass spectroscopic analysis. These studies revealed the formation of a single species in which the piperazinyl nitrogen and the -COOH group attached to the benzoxazine ring system of quinolone were involved in co-ordination to the Re(CO)(3) core. The HPLC elution pattern and retention time of the Re(CO)(3)-LVX complex were comparable to those of the corresponding (99m)Tc(CO)(3)-complex proving their similarity. When incubated in isotonic saline and serum up to 24 h (99m)Tc(CO)(3)-labeled fluoroquinolones exhibited good in vitro stability. Biodistribution studies performed at different time points on rats intramuscularly infected with S. aureus as well as on rats with sterile inflammation revealed a higher uptake in the infected area than the turpentine induced inflamed area. The uptake in infected thigh was significant with (99m)Tc(CO)(3)-OFX followed by (99m)Tc(CO)(3)-LVX. The mean ratios of the uptake in infected/non-infected thighs were 4.75 and 4.27 at 8 h and 24 h, respectively, for (99m)Tc(CO)(3)-OFX and 4.42 and 4.18 at 24 h and 8 h, respectively, for (99m)Tc(CO)(3)-LVX. The above abscess to muscle ratios were higher than reported for (99m)Tc-ciprofloxacin and other (99m)Tc-labeled fluoroquinolones. Scintigraphy studies also showed a significant uptake in the infectious lesions suggesting that (99m)Tc(CO)(3)-fluoroquinolones might be useful as diagnostic agents for targeted delivery in bacterial infection.

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The aim of this study was to radiolabel ciprofloxacin (Cip) and nitrofuryl thiosemicarbazone (NFT) with the fac-[(99m)Tc(CO)(3)(H(2)O)(3)](+) core and to evaluate the ability of the radiopharmaceuticals as tracers in detecting sites of infection. Cip and NFT were radiolabeled with the fac-[(99m)Tc(CO)(3)(H(2)O)(3)](+) core and characterized by RHPLC. The stabilities of the preparations were evaluated in saline and rat serum. In vitro binding studies of the radiopharmaceuticals with S. aureus were performed. Biodistribution studies were conducted at different time points after injecting (i.v.) the radiopharmaceuticals in rats (intramuscularly infected with S. aureus) as well as in rats with sterile inflammation. To assess the infection targeting capacity of (99m)Tc-tricarbonyl ciprofloxacin and nitrofuryl thiosemicarbazone, (99m)Tc(v)O-Cip and (99m)Tc(v)O-NFT were used as control. Scintigraphic imaging studies of tricarbonyl compounds and (99m)Tc(v)O-Cip were performed at 4 h after injection. The radiochemical purities of (99m)Tc(CO)(3)-Cip and (99m)Tc(CO)(3)-NFT were between 97-98% as determined by thin layer chromatography (TLRC) and RHPLC; no further purification is necessary before injection. The radiopharmaceuticals exhibited substantial stability when incubated in isotonic saline and serum up to 24 h. Biodistribution studies showed maximum uptake in the infected rat thigh muscle at 4 h post injection and washing out at slower rate from the infected site than the oxo technetium chelate. The mean ratios of uptake in infected/non-infected thighs were 3.87:1, 3.41:1 and 3.17:1 for (99m)Tc(CO)(3)-Cip, (99m)Tc(CO)(3)-NFT and (99m)Tc(v)O-Cip respectively. During scintigraphic studies, infection sites appeared quite distinctly with (99m)Tc(CO)(3)-Cip and (99m)Tc(CO)(3)-NFT, comparable to the behaviour with (99m)Tc(v)O-Cip. These results encouraged us for further development of infection imaging radiopharmaceuticals based on the (99m)Tc-tricarbonyl core.