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Synthesis and Evaluation of Novel Norfloxacin Isonitrile ^99mTc Complexes as Potential Bacterial Infection Imaging Agents.

ABSTRACT: To develop potential technetium-99m single-photon emission computed tomography (SPECT) imaging agents for bacterial infection imaging, the novel norfloxacin isonitrile derivatives CN4NF and CN5NF were synthesized and radiolabeled with a [^99mTc][Tc(I)]⁺ core to obtain [^99mTc]Tc-CN4NF and [^99mTc]Tc-CN5NF. These compounds were produced in high radiolabeling yields and showed hydrophilicity and good stability in vitro. The bacterial binding assay indicated that [^99mTc]Tc-CN4NF and [^99mTc]Tc-CN5NF were specific to bacteria. Compared with [^99mTc]Tc-CN4NF, biodistribution studies of [^99mTc]Tc-CN5NF showed a higher uptake in bacteria-infected tissues than in turpentine-induced abscesses, indicating that [^99mTc]Tc-CN5NF could distinguish bacterial infection from sterile inflammation. In addition, [^99mTc]Tc-CN5NF had higher abscess/blood and abscess/muscle ratios. SPECT image of [^99mTc]Tc-CN5NF showed that there was a clear accumulation in the infection site, suggesting that it could be a potential bacterial infection imaging radiotracer.

SUBMITTER: Fang S

PROVIDER: S-EPMC8069222 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:99mTc(CO)3-nitrilotriacetic acid, 99mTc(CO)3(NTA), is a new renal tubular agent with pharmacokinetic properties comparable to those of 131I-OIH but the clearance of 99mTc(CO)3(NTA) and 131I-OIH is still less than the clearance of PAH, the gold standard for the measurement of effective renal plasma flow. At physiological pH, dianionic 99mTc(CO)3(NTA) has a mononegative inner metal-coordination sphere and a mononegative uncoordinated carboxyl group. To evaluate alternate synthetic approaches, we assessed the importance of an uncoordinated carboxyl group, long considered essential for tubular transport, by evaluating the pharmacokinetics of three analogs with the 99mTc(CO)3(NTA) metal-coordination sphere but with uncharged pendant groups.99mTc(CO)3 complexes with N-(2-acetamido)iminodiacetic acid (ADA), N-(2-hydroxyethyl)iminodiacetic acid (HDA) and N-(fluoroethyl)iminodiacetic acid (FEDA) were prepared using a tricarbonyl kit and isolated by HPLC. The pharmacokinetics were evaluated in Sprague-Dawley rats, with 131I-OIH as an internal control; urine was analyzed for metabolites. Plasma protein binding and erythrocyte uptake were determined from the 10min blood samples. Re(CO)3(FEDA), the analog of 99mTc(CO)3(FEDA), was prepared and characterized.99mTc(CO)3(ADA), 99mTc(CO)3(HDA) and 99mTc(CO)3(FEDA) were efficiently prepared as a single species with high radiochemical purities (>99%). These new monoanionic 99mTc(CO)3 tracers with uncharged dangling groups all showed rapid blood clearance and high specificity for renal excretion. Activity in the urine, as a percent of 131I-OIH at 10 and 60min, was 96% and 99% for ADA, 96% and 100% for HDA, and 100% and 99% for FEDA, respectively. Each new tracer was excreted unchanged in the urine. The Re(CO)3(FEDA) structure adds compelling evidence that such 99mTc(CO)3(NTA) analogs have metal-coordination spheres identical to that of 99mTc(CO)3(NTA).New tracers lacking the negatively charged pendant carboxyl group previously thought to be essential for rapid renal extraction, 99mTc(CO)3(ADA), 99mTc(CO)3(HDA) and 99mTc(CO)3(FEDA), exhibit pharmacokinetics in rats comparable to those of 99mTc(CO)3(NTA) and 131I-OIH. Furthermore, these encouraging results in rats warrant evaluation of this new tracer type in humans.

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Synthesis and Evaluation of Novel Norfloxacin Isonitrile 99mTc Complexes as Potential Bacterial Infection Imaging Agents.

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Synthesis and Evaluation of Novel Norfloxacin Isonitrile ^99mTc Complexes as Potential Bacterial Infection Imaging Agents.