Arylamides hybrids of two high-affinity sigma-2 receptor ligands as tools for the development of PET radiotracers

1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine 1 (PB28) and 2- Methoxy-5-methyl-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)butyl]benzamide 2 (RHM-1) represent leads for tumor diagnosis, given their high affinity at sigma2 receptors. With the purpose of obtaining good candidates for s2 PET tracers development, hybrid structures between 1 and 2 were designed. Excellent sigma1/sigma2 selectivities were reached when 6,7-dimethoxytetrahydroisoquinolinewas linked to an omethoxy substituted arylamide (11a, 12a, 15a), and for these benzamides an intramolecular H-bond in the active conformation at the s sites, was hypothesized. However these excellent s2 ligands were accompanied by interaction with P-gp, which may limit their use as sigma2 receptor PET agents when tumors overexpress P-gp. Compound 15a whose P-gp interaction was just moderate represents an interesting tool for the development of sigma2 PET tracers useful in tumors overexpressing P-gp.