Abstract The use of positron emission tomography (PET) in early-phase development of novel drugs targeting the central nervous system, is well established for the evaluation of brain penetration and target engagement. However, when novel targets are involved a suitable PET ligand is not always available. We demonstrate an alternative approach that evaluates the attenuation of amphetamine-induced synaptic dopamine release by a novel agonist of the orphan G-protein-coupled receptor GPR139 (TAK-041). GPR139 agonism is a novel candidate mechanism for the treatment of schizophrenia and other disorders associated with social and cognitive dysfunction. Ten healthy volunteers underwent [ 11 C]PHNO PET at baseline, and twice after receiving an oral dose of d-amphetamine (0.5 mg/kg). One of the post-d-amphetamine scans for each subject was preceded by a single oral dose of TAK-041 (20 mg in five; 40 mg in the other five participants). D-amphetamine induced a significant decrease in [ 11 C]PHNO binding potential relative to the non-displaceable component (BP ND ) in all regions examined (16–28%), consistent with increased synaptic dopamine release. Pre-treatment with TAK-041 significantly attenuated the d-amphetamine-induced reduction in BP ND in the a priori defined regions (putamen and ventral striatum: 26% and 18%, respectively). The reduction in BP ND was generally higher after the 40 mg than the 20 mg TAK-041 dose, with the difference between doses reaching statistical significance in the putamen. Our findings suggest that TAK-041 enters the human brain and interacts with GPR139 to affect endogenous dopamine release. [ 11 C]PHNO PET is a practical method to detect the effects of novel drugs on the brain dopaminergic system in healthy volunteers, in the early stages of drug development.
The process of discovering and developing new drugs is complicated. Neuroimaging methods can facilitate this process. An analysis of the conceptual bases and practical limitations of different neuroimaging modalities reveals that each technique can best address different kinds of questions. Radioligand studies are well suited to preclinical and Phase II questions when a compound is known or suspected to affect well-understood mechanisms; they are also useful in Phase IV to characterize effective agents. Cerebral blood flow studies can be extremely useful in evaluating the effects of a drug on psychological tasks (mostly in Phase IV). Glucose metabolism studies can answer the simplest questions about whether a compound affects the brain, where, and how much. Such studies are most useful in confirming central effects (preclinical and early clinical phases), in determining effective dose ranges (Phase II), and in comparing different drugs (Phase IV).
Objective: The purpose of this study was to determine the magnitude of methodologic errors when PET is used for the quantitative measurement of regional cerebral glucose metabolism (rCMRglu). Methods: Performance of the analytic tests, which are the variables in the quantitative measurement of rCMRglu with PET, was evaluated. Results: For the scanner we evaluated, failure to perform daily calibration factor calculations was the single largest source of error. In addition, any variation in the accuracy or precision of patient plasma sample pipetting or plasma glucose level determinations, will result in corresponding changes in rCMRglu. Conclusions: Quantitative measurement of rCMRglu with PET requires close attention to laboratory skills, especially proper operation and maintenance of pipettes.
Objective: This study was conducted to determine the usefulness of a normal reference value database for the detection of areas of abnormal regional cerebral glucose metabolism. The results of this quantitative analysis were compared to a qualitative analysis based only on the detection of left/right asymmetry. Methods: Ten patients with medically refractory partial complex epilepsy were studied. Metabolic rate images were generated from the patient’s plasma glucose level, FDG clearance in serial arteriolized venous blood samples and PET images calibrated to a well counter. Results: Using a threshold of greater than 20% left/right asymmetry, we found areas of hypometabolism in temporal regions of four patients. Using a threshold of 1.5 s.d. less than the mean normal value for a particular region, we found areas of hypometabolism in temporal regions of eight patients. Conclusion: We found that when images were evaluated based on a laboratory normal value database, we were able to detect twice as many areas of hypometabolism.
This article explains why technologists handling positron-emitting radionuclides may have higher measured radiation exposures than technologists working with single-photon emitting radionuclides. We will summarize measurements we have made, as well as those reported by other authors. In addition, we will describe the procedures implemented to minimize exposure.
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