Imaging neuronal pathways with 52Mn PET: Toxicity evaluation in rats

Abstract

Manganese in its divalent state (Mn 2+ ) has features that make it a unique tool for tracing neuronal pathways. It is taken up and transported by neurons in an activity dependent manner and it can cross synapses. It also acts as a contrast agent for magnetic resonance imaging (MRI) enabling visualization of neuronal tracts. However, due to the limited sensitivity of MRI systems relatively high Mn 2+ doses are required. This is undesirable, especially in long-term studies, because of the known toxicity of the metal.In order to overcome this limitation, we propose 52 Mn as a positron emission tomography (PET) neuronal tract tracer. We used 52 Mn for imaging dopaminergic pathways after a unilateral injection into the ventral tegmental area (VTA), as well as the striatonigral pathway after an injection into the dorsal striatum (STR) in rats. Furthermore, we tested potentially noxious effects of the radioactivity dose with a behavioral test and histological staining. 24 h after 52 Mn administration, the neuronal tracts were clearly visible in PET images and statistical analysis confirmed the observed distribution of the tracer. We noticed a behavioral impairment in some animals treated with 170 kBq of 52 Mn, most likely caused by dysfunction of dopaminergic cells. Moreover, there was a substantial DNA damage in the brain tissue after applying 150 kBq of the tracer. However, all those effects were completely eliminated by reducing the 52 Mn dose to 20-30 kBq. Crucially, the reduced dose was still sufficient for PET imaging.

Manganese Enhanced MRI for Use in Studying Neurodegenerative Diseases

“…The half-life of 5.6 days, of the positron emitter 52 Mn allows its use in longitudinal biodistribution studies in the body and brain (Topping et al, 2013; Graves et al, 2015; Brunnquell et al, 2016; Hernandez et al, 2017; Napieczynska et al, 2017; Saar et al, 2018). MEMRI studies have shown that following systemic administration, the final distribution of manganese in the brain that allows anatomical structures was achieved 24 h after infusion.…”

“…By 4 days later 52 Mn 2+ could be traced to the amygdala and prefrontal areas of the cortex (Figure 2). Nepieczynska et al (Napieczynska et al, 2017) showed imaging of the dopaminergic and striatonigral pathways in rats 24 h after direct injection of 52 Mn 2+ into the ventral tegmental area and the dorsal striatum, respectively. The ability of 52 Mn 2+ to follow neuronal pathways after direct injection of the 52 Mn 2+ PET tracer to a specific area in the brain similar to MEMRI, can be used to study all the neuronal pathways already studied with MEMRI such as the visual and BG pathways (Pautler et al, 1998; Watanabe et al, 2001; Murayama et al, 2006).…”

Anatomy, Functionality, and Neuronal Connectivity with Manganese Radiotracers for Positron Emission Tomography

“…Connections to the prefrontal areas could also be detected after a few days. In a recent paper, Mn-52 was used to image the dopaminergic and striatonigral pathways in rats 24 h after tracer injection into the ventral tegmental area and the dorsal striatum, respectively [37]. The ability to follow neuronal connections in the brain following targeted administration of [ 52 Mn]Mn 2+ to a specific area can be expanded to many other neuronal pathways that have been demonstrated with MEMRI, e.g.…”

“…In recent years, there has been a renewed interest in using radioactive manganese for PET imaging, in particular manganese-52 [32][33][34][35][36][37]. Mn-52 is a positron emitter with a long halflife of 5.6 days, which allows longitudinal biodistribution studies in the body and brain.…”

Manganese in PET imaging: Opportunities and challenges

“…In addition, the authors stated that [ 52g Mn]MnCl 2 , although not suitable in this case, still holds promise as a radiotracer for specific uptake in the salivary glands and pancreas. Another publication evaluated 52g Mn for neuroimaging by stereotactic injection into the rat brain . The neuronal pathways between rat brain regions could be imaged successfully.…”