Targeting Metal-Aβ Aggregates with Bifunctional Radioligand [¹¹C]L2‑b and a Fluorine-18 Analogue [¹⁸F]FL2‑b

Interest in quantifying metal-Aβ species <i>in vivo</i> led to the synthesis and evaluation of [¹¹C]­L2-b and [¹⁸F]­FL2-b as radiopharmaceuticals for studying the metallobiology of Alzheimer’s disease (AD) using positron emission tomography (PET) imaging. [¹¹C]­L2-b was synthesized in 3.6% radiochemical yield (nondecay corrected, <i>n</i> = 3), >95% radiochemical purity, from the corresponding desmethyl precursor. [¹⁸F]­FL2-b was synthesized in 1.0% radiochemical yield (nondecay corrected, <i>n</i> = 3), >99% radiochemical purity, from a 6-chloro pyridine precursor. Autoradiography experiments with AD positive and healthy control brain samples were used to determine the specificity of binding for the radioligands compared to [¹¹C]­PiB, a known imaging agent for β-amyloid (Aβ) aggregates. The <i>K</i>_d for [¹¹C]­L2-b and [¹⁸F]­FL2-b were found to be 3.5 and 9.4 nM, respectively, from those tissue studies. Displacement studies of [¹¹C]­L2-b and [¹⁸F]­FL2-b with PiB and AV-45 determined that L2-b binds to Aβ aggregates differently from known radiopharmaceuticals. Finally, brain uptake of [¹¹C]­L2-b was examined through microPET imaging in healthy rhesus macaque, which revealed a maximum uptake at 2.5 min (peak SUV = 2.0) followed by rapid egress (<i>n</i> = 2)