[18F]BCPP-EF

[¹⁸F]BCPP-BF and [¹⁸F]BCPP-EF are PET probes used to evaluate mitochondrial function by targeting MC-I. Clinical studies on [¹⁸F]BCPP-EF have been reported, particularly brain studies. However, no reports exist on the use of [¹⁸F]BCPP-BF in humans. Therefore, in this study, we aimed to apply [¹⁸F]BCPP-BF to humans for the first time to assess its safety and radiation dose. We also aimed to explore the whole-body distribution of both probes by comparing the data acquired from the same participants.

Ten healthy participants underwent whole-body PET/CT measurements of [¹⁸F]BCPP-BF (117.0-153.8 MBq/body) for 90 min. Approximately 2-3 weeks after the measurements, the participants underwent [¹⁸F]BCPP-EF (109.2-158.8 MBq/body) measurements. Thirteen volumes of interest (VOIs) were manually drawn on the brain and peripheral organs using PET/CT images to evaluate the distribution and kinetics of the probes. The equivalent dose for each organ and the whole-body effective dose for each participant were calculated according to the Medical Internal Radiation Dose schema using OLINDA/EXM software.

The highest radiation doses from the administration of [¹⁸F]BCPP-BF were observed in the small intestine (65.5 ± 8.7 μGy/MBq), and the estimated effective dose (16.3 ± 2.3 μSv/MBq) was well-tolerated. There were no clinically significant safety concerns. A high accumulation of [¹⁸F]BCPP-BF was observed in the kidney, pancreas, and heart, consistent with the findings in previously reported animal studies. The distributions of both tracers were similar. However, the kinetics of [¹⁸F]BCPP-BF were different, with higher uptake and slower washout in the kidney and pancreas, and lower uptake and slower washout in the brain and liver, from those of [¹⁸F]BCPP-EF.

[¹⁸F]BCPP-BF is safe and acceptable for clinical use owing to its low toxicity and radiation dose. [¹⁸F]BCPP-BF and [¹⁸F]BCPP-EF generally exhibited similar whole-body distributions; however, their organ-specific kinetics differed slightly. The appropriate selection of these probes can provide a more accurate assessment of human mitochondrial function.

We developed three novel positron‐emission tomography (PET) probes, 2‐tert‐butyl‐4‐chloro‐5‐{6‐[2‐(2[18F]fluoroethoxy)‐ethoxy]‐pyridin‐3‐ylmethoxy}‐2H‐pyridazin‐3‐one ([18F]BCPP‐EF), 2‐tert‐butyl‐4‐chloro‐5‐[6‐(4‐[18F]fluorobutoxy)‐pyridin‐3‐ylmethoxy]‐2H‐pyridazin‐3‐one ([18F]BCPP‐BF), and 2‐tert‐butyl‐4‐chloro‐5‐{6‐[2‐(2‐[11C]methoxy‐ethoxy)‐ethoxy]‐pyridin‐3‐ylmethoxy}‐2H‐pyridazin‐3‐one ([11C]BCPP‐EM), for quantitative imaging of mitochondrial complex 1 (MC‐1) activity in vivo. These three PET probes were successfully labeled by nucleophilic [18F]fluorination or by [11C]methylation 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 [18F]BCPP‐BF, intermediate in [11C]BCPP‐EM, and low in [18F]BCPP‐EF. The kinetics of [18F]BCPP‐EF and [11C]BCPP‐EM provided a reversible binding pattern, whereas [18F]BCPP‐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 [18F]BCPP‐EF could be a useful PET probe for quantitative imaging of MC‐1 activity in the living brain by PET.