Evaluation of [¹⁸F]PF-06455943 as a Potential LRRK2 PET Imaging Agent in the Brain of Nonhuman Primates

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the common causes of inherited Parkinson's disease (PD) and emerged as a causative PD gene. Particularly, LRRK2-Gly2019Ser mutation was reported to alter the early phase of neuronal differentiation, increasing cell death. Selective inhibitors of LRRK2 kinase activity were considered as a promising therapeutic target for PD treatment. However, the development of effective brain-penetrant LRRK2 inhibitors remains challenging. Recently, we have developed a novel positron emission tomography (PET) radioligand for LRRK2 imaging and demonstrated preferable tracer properties in rodents. Herein, we evaluate [ 18 F]PF-06455943 quantification methods in the nonhuman primate (NHP) brain using full kinetic modeling with radiometabolite-corrected arterial blood samples, and homologous blocking with two doses (0.1 and 0.3 mg/kg). Kinetic analysis results demonstrated that a two-tissue compartmental model and a Logan graphical analysis are appropriate for [ 18 F]PF-06455943 PET quantification. In addition, we observed that total distribution volume (V T ) values can be reliably estimated with as short as a 30 min scan duration. Homologous blocking studies confirmed the specific binding of [ 18 F]PF-06455943 and revealed that the nonradioactive mass of PF-06455943 achieved 45−55% of V T displacement in the whole brain. This work supports the translation of [ 18 F]PF-06455943 PET imaging for the human brain and target occupancy studies.

Preliminary Exploration of Pseudo-CT-Based Attenuation Correction for Simultaneous PET/MRI Brain Imaging in Nonhuman Primates

“…The 2TCM was used to estimate the V T for [ 18 F]­PF-06455943 with the metabolite-corrected arterial plasma data, with the assumption that the blood volume is a constant (5%) for all ROIs. In the previous study, the 2TCM was determined to be the most suitable model for quantitative mapping of [ 18 F]­PF-06455943. , Occupancies (%Occ) with unlabeled PF-06455943 were calculated by dividing the reduction of [ 18 F]­PF-06455943 V T value by homologous blocking with 0.1 or 0.3 mg/kg of unlabeled PF-06455943 ( V T, Baseline – V T, Blocking ) by the baseline V T value, respectively. For [ 11 C]­OMAR B/I analysis, the JIP tools were used to calculate the nondisplaceable binding potential before (BP ND, Baseline ) and after (BP ND, Blocking ) rimonabant challenge using the occipital gyrus as a reference region.…”

“…We compared a segmentation-based AC method with our template-based AC approach using two experimental paradigms: (1) Utilizing the novel radiotracer [ 18 F]­PF-06455943, baseline-blocking PET scans were acquired with arterial blood samples on two separate imaging sessions. The [ 18 F]­PF-06455943 radiotracer was previously used in the NHP brains and demonstrated favorable kinetic properties for the calculation of kinetic parameters using the two-tissue compartment (2TCM) and favorable volume of distribution ( V T ) displacement of 45–55% throughout the brain by the homologous blocking. , (2) We performed a B/I study using the radiotracer [ 11 C]­OMAR, which binds to cannabinoid type 1 receptor (CB1R) while administering an antagonist (rimonabant). In the B/I study, the receptor occupancy of an antagonist was determined.…”

“…The [ 18 F]PF-06455943 radiotracer was previously used in the NHP brains and demonstrated favorable kinetic properties for the calculation of kinetic parameters using the two-tissue compartment (2TCM) and favorable volume of distribution (V T ) displacement of 45−55% throughout the brain by the homologous blocking. 19,20 (2) We performed a B/ I study using the radiotracer [ 11 C]OMAR, which binds to cannabinoid type 1 receptor (CB1R) while administering an antagonist (rimonabant). In the B/I study, the receptor occupancy of an antagonist was determined.…”