Radiochemical Approaches to Imaging Bacterial Infections: Intracellular versus Extracellular Targets

Abstract

The discovery of penicillin began the age of antibiotics, which was a turning point in human healthcare. However, to this day, microbial infections are still a concern throughout the world, and the rise of multidrug-resistant organisms is an increasing challenge. To combat this threat, diagnostic imaging tools could be used to verify the causative organism and curb inappropriate use of antimicrobial drugs. Nuclear imaging offers the sensitivity needed to detect small numbers of bacteria in situ. Among nuclear imaging tools, radiolabeled antibiotics traditionally have lacked the sensitivity or specificity necessary to diagnose bacterial infections accurately. One reason for the lack of success is that the antibiotics were often chelated to a radiometal. This was done without addressing the ramifications of how the radiolabeling would impact probe entry to the bacterial cell, or the mechanism of binding to an intracellular target. In this review, we approach bacterial infection imaging through the lens of bacterial specific molecular targets, their intracellular or extracellular location, and discuss radiochemistry strategies to guide future probe development.

New synthesis of 6″‐[18F]fluoromaltotriose for positron emission tomography imaging of bacterial infection

“…Elevated reaction temperature in MeCN from 85 C to 125 C increased the radiochemical yield from 1.4% to 3.5%; however, a minimal impact on the yield was observed in DMF upon increasing the reaction temperature ( Table 1). The loss in 18 F incorporation in the radiofluorination step is a potential factor that corresponds to the variation in the radiochemical yields in different solvents and temperatures. Direct fluorination of 15 in acetonitrile for 20 min at 125 C afforded the highest radiochemical yield in comparison with other conditions ( Amide OBD Prep Column, 130 Å, 3.5 μm, 4.6 × 250 mm) with the mobile phase water/acetonitrile (30/70) and flow rate of 1 ml/min using a radioactive detector and Corona Veo charged aerosol detector (CAD) (SKU:5081.0010) ( Figure 2).…”

“…The retention of the newly synthesized 6 00 -[ 18 F]fluoromaltotriose in E. coli comes in good agreement with that of the previously reported tracer (47% retention vs. 50% retention). 28,29 F I G U R E 2 Coinjection of 6 00 -[ 18 Additionally, the new tracer was evaluated in an E. coliinduced myositis model where E. coli was administered to the right thigh of mice as an intramuscular injection as previously described. 28 As shown in Figure 4, the newly synthesized tracer was capable of differentiating between infected muscle from the uninfected contralateral muscle (p < 0.05), similar to the previous tracer synthesis approach.…”

“…However, single-photon emission computer tomography (SPECT) and positron emission tomography (PET) modalities represent powerful tools for imaging of bacterial infections in the clinic as they enable whole body imaging with high spatial resolution. [16][17][18][19] For example, Figure 1) has been developed as a PET tracer for imaging bacterial infection via targeting bacterial thymidine kinase (TK). 20 However, the insufficient selectivity of the PET tracer 1 for bacterial TK over mammalian TK limits its potential use in bacteria-specific imaging.…”

“…29 The synthetic route for the previously reported maltotriose nosylate precursor features ambiguous assignment of the position of the nosylate group on maltotriose and subsequently the fluorine-18 position due to the lack of a validated route for selective monoprotection of primary hydroxyl groups in maltotriose ( Figure S1). Herein, we report a new synthesis of 6 00 -[ 18…”

Imaging Bacteria with Radiolabelled Probes: Is It Feasible?

“…The main limits include a low specificity, low bacterial mass, unclear mechanisms of action, the presence of biofilm that limits their penetration and the host immune response. Moreover, the location of the bacterial target influences the choice of radiopharmaceuticals and its development [18][19][20][21].…”