Preparation and in vivo characterization of 51MnCl2 as PET tracer of Ca2+ channel-mediated transport

Abstract

Manganese has long been employed as a T₁-shortening agent in magnetic resonance imaging (MRI) applications, but these techniques are limited by the biotoxicity of bulk-manganese. Positron emission tomography (PET) offers superior contrast sensitivity compared with MRI, and recent preclinical PET studies employing ^52gMn (t_1/2: 5.6 d, β⁺: 29%) show promise for a variety of applications including cell tracking, neural tract tracing, immunoPET, and functional β-cell mass quantification. The half-life and confounding gamma emissions of ^52gMn are prohibitive to clinical translation, but the short-lived ⁵¹Mn (t_1/2: 46 min, β⁺: 97%) represents a viable alternative. This work develops methods to produce ⁵¹Mn on low-energy medical cyclotrons, characterizes the in vivo behavior of ⁵¹MnCl₂ in mice, and performs preliminary human dosimetry predictions. ⁵¹Mn was produced by proton irradiation of electrodeposited isotopically-enriched ⁵⁴Fe targets. Radiochemically isolated ⁵¹MnCl₂ was intravenously administered to ICR mice which were scanned by dynamic and static PET, followed by ex vivo gamma counting. Rapid blood clearance was observed with stable uptake in the pancreas, kidneys, liver, heart, and salivary gland. Dosimetry calculations predict that 370 MBq of ⁵¹Mn in an adult human male would yield an effective dose equivalent of approximately 13.5 mSv, roughly equivalent to a clinical [¹⁸F]-FDG procedure.

Figure 1

(A) Concentration of Fe in electrodeposition solution as a function of time (red) and solution pH as a function of time (blue). Fe concentration was measured by microwave plasma atomic emission spectroscopy (MP-AES). (B) Plating current as a function of time with plating potential held constant at 7.0 ± 0.1 V. (C) Photograph of plating cell at the start of plating. During plating the light green color becomes colorless. (D) Photograph of electroplated ⁵⁴Fe target on Ag disc substrate.

Figure 2

Dynamic PET time-activity curves (TACs) of organ ROIs in ICR mice (n = 2, mean ± SD) injected with a rapid intravenous bolus of ⁵¹Mn(II), imaged for 30 minutes post-injection.

Figure 3

(A) Coronal slice and maximum intensity projection (MIP) static PET images of a representative ICR mouse injected intravenously with ⁵¹Mn(II) (non-anaesthetized during injection). PET images were acquired one hour post-injection. Pancreas (P), salivary gland (SG), heart (H), liver (L) and kidneys (K) indicated by arrows. (B) ⁵¹Mn tissue uptake quantification of hand-drawn PET ROIs in ICR mice (n = 3, mean ± SD) injected with a rapid intravenous bolus of ⁵¹Mn(II). (C) Ex vivo ⁵¹Mn biodistribution in ICR mice (n = 3, mean ± SD) immediately following PET imaging, measured by gamma counting.