The biodistribution of 5-[18F]fluoropyrazinamide in Mycobacterium tuberculosis-infected mice determined by positron emission tomography.

5-[18F]F-pyrazinamide (5-[18F]F-PZA), a radiotracer analog of the first-line tuberculosis drug pyrazinamide (PZA), was employed to determine the biodistribution of PZA using PET imaging and ex vivo analysis. 5-[18F]F-PZA was synthesized in 60 min using a halide exchange reaction. The overall decay-corrected yield of the reaction was 25% and average specific activity was 2.6 × 106 kBq (70 mCi)/μmol. The biodistribution of 5-[18F]F-PZA was examined in a pulmonary Mycobacterium tuberculosis mouse model, where rapid distribution of the tracer to the lung, heart, liver, kidney, muscle, and brain was observed. The concentration of 5-[18F]F-PZA was not significantly different between infected and uninfected lung tissue. Biochemical and microbiological studies revealed substantial differences between 5-F-PZA and PZA. 5-F-PZA was not a substrate for pyrazinamidase, the bacterial enzyme that activates PZA, and the minimum inhibitory concentration for 5-F-PZA against M. tuberculosis was more than 100-fold higher than that for PZA

Analytical HPLC chromatography of 5-[¹⁸F]F-PZA.

<p>(A) HPLC chromatography of purified 5-[¹⁸F]F-PZA. The blue trace is the UV absorption of the eluent at 254 nm from an injection of purified 5-[¹⁸F]F-PZA. The red trace is the radioactive signal of the injected 5-[¹⁸F]F-PZA. (B) Co-injection of standard 5-F-PZA with purified 5-[¹⁸F]F-PZA. The blue trace is the UV absorption of the eluent at 254 nm of purified 5-[¹⁸F]F-PZA spiked with cold standard 5-F-PZA. The red trace is the radioactive signal of the purified 5-[¹⁸F]F-PZA spiked with cold standard 5-F-PZA.</p

[11C]Para-Aminobenzoic Acid: A Positron Emission Tomography Tracer Targeting Bacteria-Specific Metabolism.

Imaging studies are frequently used to support the clinical diagnosis of infection. These techniques include computed tomography (CT) and magnetic resonance imaging (MRI) for structural information and single photon emission computed tomography (SPECT) or positron emission tomography (PET) for metabolic data. However, frequently, there is significant overlap in the imaging appearance of infectious and noninfectious entities using these tools. To address this concern, recent approaches have targeted bacteria-specific metabolic pathways. For example, radiolabeled sugars derived from sorbitol and maltose have been investigated as PET radiotracers, since these are efficiently incorporated into bacteria but are poor substrates for mammalian cells. We have previously shown that para-aminobenzoic acid (PABA) is an excellent candidate for development as a bacteria-specific imaging tracer as it is rapidly accumulated by a wide range of pathogenic bacteria, including metabolically quiescent bacteria and clinical strains, but not by mammalian cells. Therefore, in this study, we developed an efficient radiosynthesis for [11C]PABA, investigated its accumulation into Escherichia coli and Staphylococcus aureus laboratory strains in vitro, and showed that it can distinguish between infection and sterile inflammation in a murine model of acute bacterial infection

[11C]Para-Aminobenzoic Acid: A Positron Emission Tomography Tracer Targeting Bacteria-Specific Metabolism

Imaging studies are frequently used to support the clinical diagnosis of infection. These techniques include computed tomography (CT) and magnetic resonance imaging (MRI) for structural information and single photon emission computed tomography (SPECT) or positron emission tomography (PET) for metabolic data. However, frequently, there is significant overlap in the imaging appearance of infectious and noninfectious entities using these tools. To address this concern, recent approaches have targeted bacteria-specific metabolic pathways. For example, radiolabeled sugars derived from sorbitol and maltose have been investigated as PET radiotracers, since these are efficiently incorporated into bacteria but are poor substrates for mammalian cells. We have previously shown that para-aminobenzoic acid (PABA) is an excellent candidate for development as a bacteria-specific imaging tracer as it is rapidly accumulated by a wide range of pathogenic bacteria, including metabolically quiescent bacteria and clinical strains, but not by mammalian cells. Therefore, in this study, we developed an efficient radiosynthesis for [11C]PABA, investigated its accumulation into Escherichia coli and Staphylococcus aureus laboratory strains in vitro, and showed that it can distinguish between infection and sterile inflammation in a murine model of acute bacterial infection

Synthesis of reference 5-F-PZA.

<p>Synthesis of reference 5-F-PZA.</p

Dynamic PET/CT imaging of 5-[¹⁸F]F-PZA in infected and uninfected mice.

<p>(A) Dynamic PET/CT images of a representative <i>M</i>. <i>tuberculosis</i>-infected mouse. Lung consolidations (yellow arrows) can be observed in the transverse and coronal CT sections. PET/CT images 0 to 10 min, 20 to 30 min and 50 to 60 min post tracer administration. (B) Dynamic PET/CT images of a representative uninfected control mouse. The images showed in the figure are representatives of 3 animals. H = heart.</p

Radiosynthesis of 2-[¹⁸F]F-PZA.

<p>Radiosynthesis of 2-[¹⁸F]F-PZA.</p

Wayne’s modified pyrazinamidase assay.

<p>Wayne’s modified pyrazinamidase assay.</p

A Multi-center Genome-wide Association Study of Cervical Dystonia

Background: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility. Objective: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach. Methods: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal. Results: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10−8). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10−6). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value&nbsp;=&nbsp;3.07 × 10−8, minor allele frequency&nbsp;=&nbsp;0.01), located within the GABBR2 gene on chromosome 9 (rs147331823). Conclusion: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society