Binding affinity profiles of isoquinoline carboxamide and phenoxyphenyl acetamide-based TSPO PET ligands in human brain and heart

Objectives: With the exception of PK11195, current generation Positron Emission Tomography (PET) translocator protein (TSPO) ligands display rs6971 genotype-dependent binding affinity. Recently, we developed a novel TSPO ligand, AB5186, based on the PK11195 isoquinoline structure[1] (Fig. 1A). This study aimed to evaluate and compare the binding affinity of PK11195, AB5186 and the phenoxyphenylacetamide-based PBR28 in human brain and heart tissue samples.

Methods: Human brain and heart tissue samples were screened to determine their rs6971 genotype and grouped into high (HAB), mixed (MAB) and low (LAB) affinity binders. Competition binding assays were performed in triplicate for each TSPO ligand based on previously described methodology[2].

Results: In brain, the Ki LAB/HAB ratios were: 1.0, 9.7 and 50.1 for PK11195, AB5186 (Fig. 1B) and PBR28, respectively (n=3-8). In heart, the Ki LAB/HAB ratios were: 0.6, 7.0 and 49.7 for PK11195, AB5186 (Fig. 1C) and PBR28 respectively (n=2). MAB showed intermediate Ki values for both brain and heart.

Conclusion: In contrast with previously published data[3], binding profiles are analogous in brain and heart. For the first time, we show that binding of the isoquinoline-based ligand AB5186, although structurally similar to PK11195, is susceptible to the rs6971 genotype. Research Support: Work funded by the British Heart Foundation (PG/16/12/32022).