PROJECT SUMMARY Millions of middle-aged and seniors in the United States maintain their blood pressure and prevent cardiovascular emergencies by taking - and -blockers daily. The total global market grew to $20 B for these drugs in 2017. These two important drug classes commonly target adrenergic receptors (ARs) that execute critical physiological functions such as respiration, digestion, circulation, emotion, memory, and cognition mediated by norepinephrine (NE). Many - and -blockers bind nonspecifically to ARs and do not only produce pharmaceutical effects but also accompany critical side effects. Therefore, subtype-selective AR agonists and antagonists can achieve the desired goals without inducing the side effects. Such a request for the two drug classes has been largely ignored. Among the nine subtypes of ARs, the biologic properties of 2C-ARs drew interest in the pharmaceutical industry. The presynaptic 2C-ARs regulate the release of NE, dopamine, and serotonin to the synapse. The brain 2C-ARs mainly concentrate in the limbic regions, such as the striatum and hippocampus. Taking these properties together, the 2C-ARs can selectively control the neurotransmitter levels in the limbic regions without affecting the levels in the prefrontal regions. Alzheimer’s disease (AD) features neuronal loss in the hippocampus, where 2C-ARs are abundant and might be changed by the noradrenergic neurons projected from locus coeruleus, the first brain system affected by AD. In substance use disorder (SUD), activation of the 2C-ARs can reduce the neuronal hyperactivity in the limbic regions without affecting the brain circuit toward the prefrontal cortex, which inhibits the instinctive behavior toward brain stimulants and facilitates rational judgment against them. Therefore, 2C-ARs can be a good drug target, and their positron emission tomography (PET) radiotracer can monitor their biological properties under various disease conditions. [11C]ORM13070 is an important milestone because this is the first successful subtype-specific AR radiotracer among their nine subtypes. However, its pharmacokinetic properties and specificities have to be improved. The current project will develop the first fluorine-18 (F-18) 2C-AR radiotracers and evaluate them by comparing their properties with [11C]ORM13070. We designed various 1,4-benzodioxane derivatives based on ORM13070. The current strategy based on the existing molecular frame reduces the risk of failure and increases the success of the development with short-term funding. The experience will eventually lead to future development based on a new molecular framework. The current project selected seven candidate compounds using a computer-aided docking model study. These compounds will be synthesized, and receptor-binding assays will further select the compounds. After the target radiotracers are prepared, preclinical PET imaging studies will evaluate them. The PET imaging data will also be validated by auto...