Pharmacological agonists for more-targeted CNS radio-pharmaceuticals

G-protein-coupled brain receptors provide abundant targets for psychotropic drugs and have been widely explored by PET (positron-emission tomography) brain imaging. PET is a nuclear medicine technique consisting in injecting molecules that have been radiolabeled with positron-emitters such as fluoride-18 or carbon-11. When such radiotracers can be implemented in animal models or humans, they are known as radiopharmaceuticals [1]. Around 800 G-protein-coupled receptors have been identified in the man, but specific PET radiopharmaceuticals are presently available for few of these potential therapeutic targets. Developing a validated radiopharmaceutical enabling a brain receptor to be visualized and quantified involves a certain number of criteria, both radiochemical and radiopharmacological [2]. Chemically, the molecule in question, which is often a low-molecular-weight heterocycle, needs to be able to be radiolabeled: i.e., have an atom or chemical group that can be replaced by an atom of fluoride-18 or carbon-11. The short radioactive halflife of these isotopes (respectively, 110 and 20 minutes) requires a rapid radiolabeling method involving a minimal number of steps, validated pharmaceutically before injection under the PET camera. Radiopharmacologically, two main criteria are to be met: rapid brain penetration to enable quick acquisition after intravenous injection; and good specificity, with high affinity for the targeted receptor and very low affinity for any rival target or non-specific binding. If the fixation rate is low, with fewer than 5% of receptors occupied, such a “tracer” dose has to target a single protein. It is mainly because of this requirement of targetspecificity that most PET radiopharmaceuticals developed to target receptors are, pharmacologically, antagonists. The range of antagonist molecules is wide, and many show satisfactory specificity and fixation suitable for PET brain imaging (kon > koff). In-vitro pharmacologic studies, however, show that antagonists bind to both G-proteincoupled (i.e., functional) receptors and to non-functional non-G-coupled receptors of the same family [3]. Agonists, on the other hand, bind preferentially to G-protein-coupled (functional) receptors (Figure 1). The objective is to apply these pharmacologic findings to in vivo imaging, with the hypothesis that developing both an antagonist and an agonist radiopharmaceutical for the same receptor would enable two distinct cerebral fixation patterns, aimed at the same target, to be compared [4]. The serotoninergic system is especially well suited to this original radiopharmacologic strategy. 5-HT1A family serotoninergic receptors are involved in numerous physiological (thermoregulation, respiration, sleep, memory, cognition, etc.) and pathological processes (mood disorder, anxiety, involuntary movement, apnea, etc.), making the 5-HT1A receptor an interesting target for psychopharmacology and, more recently, neuropharmacology. Several PET 5-HT1A radiopharmaceuticals ([11C]-WAY-100635, [18F]-FCWAY, [18F]-MPPF, etc.) are currently used in humans, but all are Editorial: Neuroscience