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Reduced <sup>18</sup>F‑Folate Conjugates as a New Class of PET Tracers for Folate Receptor Imaging
5-Methyltetrahydrofolate
(5-MTHF), a reduced folate form, is the
biologically active folate involved in many different metabolic processes.
To date, there are no studies available in the literature on <sup>18</sup>F-labeled 6<i>S</i>- and 6<i>R</i>-5-MTHF
radiotracers for imaging folate receptor (FR)-α-positive tissues.
Therefore, the goal of this study was to synthesize four <sup>18</sup>F-labeled 5-MTHF derivatives conjugated at either the α- or
γ-carboxylic functionality of glutamate and to assess their
suitability for FR-targeting. Organic syntheses of the precursors
and the four reference compounds, namely, 6<i>S</i>-α,
6<i>S</i>-γ, 6<i>R</i>-α, and 6<i>R</i>-γ-click-fluoroethyl-5-MTHF, were carried out in
low to moderate overall chemical yields. The radiosyntheses of the
α- and γ-conjugated <sup>18</sup>F-labeled folate derivatives
were accomplished in approximately 100 min, low radiochemical yields
(1–7% d.c.) and high molar activities (139–245 GBq/μmol).
Radiochemically pure tracers were obtained after the addition of a
mixture of antioxidants consisting of sodium ascorbate and l-cysteine. <i>In vitro</i>, all four 5-MTHF conjugates
showed similar binding affinities to FR-α (IC<sub>50</sub> =
17.7–24.0 nM), whereas folic acid showed a significantly higher
binding affinity to the FR-α. Cell uptake and internalization
experiments with KB cells demonstrated specific uptake and internalization
of the radiofolate conjugates. Metabolite studies in mice revealed
high <i>in vivo</i> stability of the radiotracers in mice.
Biodistribution and positron emission tomography (PET) imaging studies
in FR-positive KB tumor-bearing mice demonstrated that the 6<i>S</i>- and 6<i>R</i>-5-MTHF conjugates exhibited a
different accumulation pattern in various organs including the kidneys
and the liver, whereas no significant differences in radioactivity
accumulation in the kidneys and the liver were found for both the
α- and γ-conjugated diastereoisomers. Despite the considerably
lower binding affinities of the 5-MTHF derivatives compared to the
corresponding folic acid conjugates similar high KB tumor uptake was
observed for all the folate conjugates investigated (8–11%
IA/g). Based on these results, we conclude that <sup>18</sup>F-labeled
5-MTHF conjugates are a promising new class of radiotracers for targeting
FR-positive tumor tissues