Development of F-18 Labeled Radiotracers for PET Imaging of Brain Alpha-1 Noradrenergic Receptors: Potential PTSD Vulnerability and Diagnostic Biomarkers

Abstract : Increased central nervous system (CNS) alpha-1 noradrenergic receptor ( 1NAR) responsivity may be a vulnerability and/or diagnostic biomarker for posttraumatic stress disorder (PTSD). Development of 1NAR PET radiotracers would allow in vivo interrogation of CNS 1NAR responsivity in combat-exposed active duty and Veteran warriors with PTSD. During the initial period of this award, we synthesized a 6-[18-F]-Fluoro-5 -Iodo analog of the 1NAR antagonist, 1-(2H)- naphthalenone-3,4-dihydro-2-(((2-p-hydroxyphenyl)-ethylamino)-methyl)-HCl (HEAT). PET imaging studies of [18F]-fluoro-5 - iodo-HEAT binding to CNS 1NAR in 2 Macaques demostrated rapid uptake but negligible efflux of radioactivity from the brain over 120 minutes, consistent with high levels of non-specific binding. Analysis of venous plasma samples indicated that 6-[18- F]-Fluoro-5 -iodo-HEAT decomposed or was metabolised to a lipophilic product as early as four minutes after administration rendering it unsuitable for PET imaging of brain 1NAR. Subsequently, we synthesized another 8 HEAT analogs and their binding affinities for cloned human 1NARs and other neurotransmitter receptors was performed by the NIMH Psychoactive Drug Screening Pro-gram (PDSP). The HEAT analog exhibing the best profile of 1NAR vs. off-target neurotransmitter receptor binding was 6-Fluoro-5 -Iodo-HEAT, the compound we had previously found to be rapidly metabolised in vivo. Based upon these findings, we have chosen to abandon the HEAT structue as a platform for developing 1NAR radiotracers.