Development of novel PET probes, 18FBCPP‐EF, 18FBCPP‐BF, and 11CBCPP‐EM for mitochondrial complex 1 imaging in the living brain

We developed three novel positron-emission tomography (PET) probes, 2-tert-butyl-4-chloro-5-6-2- (2[ (18) Ffluoroethoxy) -ethoxy]-pyridin-3-ylmethoxy-2H-pyridazin-3-one ( (18) FBCPP-EF), 2-tert-butyl-4-chloro-5-6- (4-[ (18) Ffluorobutoxy) -pyridin-3-ylmethoxy]-2H-pyridazin-3-one ( (18) FBCPP-BF), and 2-tert-butyl-4-chloro-5-6-2- (2-[ (11) Cmethoxy-ethoxy) -ethoxy]-pyridin-3-ylmethoxy-2H-pyridazin-3-one ( (11) CBCPP-EM), for quantitative imaging of mitochondrial complex 1 (MC-1) activity in vivo. These three PET probes were successfully labeled by nucleophilic (18) Ffluorination or by (11) Cmethylation of their corresponding precursor with sufficient radioactivity yield, good radiochemical purity, and sufficiently high specific radioactivity for PET measurement. The specificity of these probes for binding to MC-1 was assessed with rotenone, a specific MC-1 inhibitor, by a rat brain slice imaging method in vitro. Rat whole-body imaging by small-animal PET demonstrated that all probes showed high uptake levels in the brain as well as in the heart sufficient to image them clearly. The rank order of uptake levels in the brain and the heart just after injection was as follows: high in (18) FBCPP-BF, intermediate in (11) CBCPP-EM, and low in (18) FBCPP-EF. The kinetics of (18) FBCPP-EF and (11) CBCPP-EM provided a reversible binding pattern, whereas (18) FBCPP-BF showed nonreversible accumulation-type kinetics in the brain and heart. Metabolite analyses indicated that these three compounds were rapidly metabolized in the plasma but relatively stable in the rat brain up to 60 min post-injection. The present study demonstrated that (18) FBCPP-EF could be a useful PET probe for quantitative imaging of MC-1 activity in the living brain by PET.