Radiosynthesis, quality control, biodistribution, and infection-imaging study of a new 99mTc-labeled ertapenem radiopharmaceutical

Abstract

Ertapenem is a member of carbapenem antibiotics used for the treatment of moderate-to-severe intra-abdominal, urinary tract, acute pelvic, and post-surgical gynecologic infections. The antibacterial activity of ertapenem is mediated through binding to penicillin-binding proteins which results in inhibiting the cross-linking of the peptidoglycan layer of the bacterial cell wall. Therefore, ertapenem can be labeled with technetium-99m (^99mTc), a gamma emitter radionuclide, for the diagnosis of deep-seated bacterial infections, such as urinary tract, intra-abdominal, osteomyelitis, and post-surgical gynecologic infections. The labeling procedure was carried out by varying the reaction conditions, such as the amount of the ligand and reducing agent, pH, reaction time and temperature, and radioactivity. At optimized reaction conditions more than 93% ^99mTc-ertapenem radioconjugate was obtained. ^99mTc-ertapenem was found 90% intact in saline medium up to 6 h, while 88% intact in human blood serum up to 3 h. Biodistribution study showed target-to-non-target ratios of 2.91 ± 0.19, 2.39 ± 0.31, and 1.23 ± 0.22 in S. aureus, E. coli, and turpentine oil-infected rat models, respectively. The SPECT scintigraphy showed high uptake of ^99mTc-ertapenem in bacterial-infected abscesses, and low counts were recorded in normal and turpentine oil-inflamed tissues. In conclusion, ^99mTc-ertapenem can be a potent infection-imaging agent, which can diagnosis deep-seated bacterial infections at early stage but need further pre-clinical evaluation in variety of infection models.

Keywords: SPECT imaging; ertapenem; infection imaging; metal complex; nuclear medicine; radiopharmaceuticals.

FIGURE 1

Chemical structure of sodium salt of ertapenem

FIGURE 2

Radio-chromatograms of radiochemical mixture analysis using ITLC: (A) determination of free ^99mTc; (B) determination hydrolyzed radioactive impurity.

FIGURE 3

(A) Effect of ligand (ertapenem) concentration on radiochemical yield; (B) effect of the reducing agent (SnCl₂•2H₂O) on radiochemical yield; (C) effect of pH on radiochemical yield; and (D) effect of reaction time on radiochemical yield.

SCHEME 1

Radiosynthesis scheme with the predictive chemical structure of ^99mTc–ertapenem.

FIGURE 4

Stability of ^99mTc–ertapenem in saline and blood serum.

FIGURE 5

Biodistribution of ^99mTc–ertapenem in; (A) S. aureus infection induced rat models, (B) E. coli infection induced rat models and, (C) inflammation induced rat models.

FIGURE 6

SPECT gamma camera scintigraphy images, at 30 min and 4 h post injection of ^99mTc-ertapenem radiopharmaceutical, of: (A) healthy rabits, (B) S. aureus infection and inflammation induced rabits, (C) E. coli infection and inflammation induced rabits and, (D) S. aureus and E.coli infection induced rabits.