To develop methods for in vivo imaging of CNS receptor and signal transduction mechanisms, radiolabeled ligands with appropriate SAR requirements are being produced and used to develop in vivo animal models, and will lead ultimately to studies in human subjects. Synthetic organic chemistry techniques are used to produce cold-labeled derivatives of candidate compounds to determine SAR in displacement assays using standard beta (C-14 or H-3) or gamma (I-125) emitting radioligands. If cold-labeled compounds retain activity, techniques are developed for rapid radiosynthesis. Positron (F-18, C-11, I-124) emitting derivatives are used in initial in vivo studies to determine blood brain barrier penetration and in vivo activity; both autoradiographic and external imaging (high resolution small animal PET) techniques are used. Tracer kinetic (bolus or equilibrium) models have been developed in rodents and primates, and validated using activation and displacement techniques.A cold-fluorinated (fluoroethyl-carbamate) derivative of forskolin was previously synthesized, and high affinity (Kd < 40 nM), saturable binding to adenylyl cyclase demonstrated in vitro. A preliminary study using an F-18 labeled derivative of this compound in rodents, using autoradiographic methods, and non-human primates, using PET has been submitted for publication. Pilot studies evaluating voltage sensitive compounds for use in PET have been completed, and studies of CNS uptake and processing of thyroid hormone, using I-124 labeled T3, have been initiated. - neuroimaging, neurochemistry, PET, radioligand, signal transduction, forskolin, adenylate cyclase, CNS