Evaluation of (99m)Tc(i)-tricarbonyl complexes of fluoroquinolones for targeting bacterial infection.
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.
Nuclear Medicine Division, Indian Institute of Chemical Biology (CSIR), 4, Raja S. C. Mullick Road, Jadavpur, Kolkata-700032, India.
Dipak Kumar
DK
Nayak
Rinku
R
Baishya
Kamal Krishna
KK
Halder
Tuhinadri
T
Sen
Bharat R
BR
Sarkar
Shantanu
S
Ganguly
M K
MK
Das
Mita Chatterjee
MC
Debnath
D000818:Animals; D004355:Drug Stability; D024841:Fluoroquinolones / Q000737:chemistry / Q000493:pharmacokinetics; D057927:Hydrophobic and Hydrophilic Interactions; D015609:Organotechnetium Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013203:Staphylococcal Infections / Q000000981:diagnostic imaging* / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000302:isolation & purification*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
D024841:Fluoroquinolones; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals