In vivo molecular imaging: ligand development and research applications

In positron emission tomography (PET) and single-photon emission computed tomography (SPECT), tracers labeled with radioactive isotopes are used to measure protein mole-cules (e.g., receptors, transporters, and enzymes). A major advantage of these two radiotracer techniques is extraordi-narily high sensitivity ( 109 to 1012 M), many orders of magnitude greater than the sensitivities available with magnetic resonance imaging (MRI) ( 104 M) or mag-netic resonance spectroscopy (MRS) ( 103 to 105 M). For example, MRI detection of gadolinium occurs at con-centrations of approximately 104 M (1), and MRS mea-sures brain levels of -aminobutyric acid (GABA) and gluta-mine at concentrations of approximately 103 M (2,3). In contrast, PET studies with [11C]NNC 756 in which a conventional bismuth germanate-based scintillator is used can measure extrastriatal dopamine D1 receptors present at a concentration of approximately 109 M (4). Because many molecules of relevance to neuropsychiatric disorders are present at concentrations of less than 108 M, radio-tracer imaging is the only currently available in vivomethod capable of quantifying these molecular targets. PET and SPECT quantify the distribution of radioactivi-ties in the brain, the direct in vivo correlates of in vitro autoradiographic film techniques such as receptor autoradi-ography, Western blots, and Northern blots. Thus, the fu-ture possibilities of radiotracer imaging are broad and excit-ing—and include targets of receptors, signal transduction, and gene expression. From this broader perspective, PET and SPECT methodologies are described as ‘‘in vivo molec-ular imaging.’’ Although in vivo molecular imaging is a promising tech-nique, several barriers — physical, monetary, and chemi-cal—to its successful application in neuropsychiatric disor