https://tauruspet.med.yale.edu/staff/edm42/IUPUI-website/emorris.tar/emorris/emorris/PETjournalCLub/simplifiedrefregionLammertsma96.pdf

Simplified Reference Tissue Model for PET Receptor Studies

https://tauruspet.med.yale.edu/staff/edm42/IUPUI-website/emorris.tar/emorris/emorris/PETjournalCLub/parametric%20imaging%20methods/Gunn%201997%20Neuroimage%20SRTM%20basis%20functions.pdf

Parametric Imaging of Ligand-Receptor Binding in PET Using a Simplified Reference Region Model

The treatment of schizophrenia has evolved over the past half century primarily in the context of antipsychotic drug development. Although there has been significant progress resulting in the availability and use of numerous medications, these reflect three basic classes of medications (conventional (typical), atypical and dopamine partial agonist antipsychotics) all of which, despite working by varying mechanisms of actions, act principally on dopamine systems. Many of the second-generation (atypical and dopamine partial agonist) antipsychotics are believed to offer advantages over first-generation agents in the treatment for schizophrenia. However, the pharmacological properties that confer the different therapeutic effects of the new generation of antipsychotic drugs have remained elusive, and certain side effects can still impact patient health and quality of life. Moreover, the efficacy of antipsychotic drugs is limited prompting the clinical use of adjunctive pharmacy to augment the effects of treatment. In addition, the search for novel and nondopaminergic antipsychotic drugs has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current therapeutic armamentarium for treating schizophrenia and drug development strategies and theories of mechanisms of action of antipsychotics, and focuses on novel targets for therapeutic agents for future drug development.

/pdf/treatments-for-schizophrenia-a-critical-review-of-1r0u7s3s3j.pdf

Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

Five different methods for the estimation of the binding potential, a measure of Bmax/Kd, of [11C]raclopride in human striatum were compared using data from a dose ranging study of the neuroleptic CP-88,059-01. Binding potential was estimated indirectly, from distribution volumes in striatum and cerebellum, using both single- and two-tissue compartment models with a metabolite-corrected plasma curve as input function. The two-tissue compartment model was also used for a direct estimate of the binding potential. In addition, a direct estimate was obtained from the reference tissue compartment model using the cerebellum as indirect input function. Finally, an estimate of binding potential was calculated from the ratio of striatum over cerebellum counts at late times after injection. The estimates of striatum binding potential from all methods, except the direct determination using a two-tissue compartment model with metabolite-corrected plasma input function, correlated with each other. Use of an average metabolite correction resulted in only a small reduction in accuracy in this series of normal subjects. The reference tissue model provided estimates of the binding potential with the same sensitivity for detecting changes as those methods that required a metabolite-corrected plasma input function. This indicates that for routine analysis of clinical [11C]raclopride studies, no arterial cannulation is required. The range of normal values was significantly less variable with the reference tissue method than when simple striatum-to-cerebellum ratios were used.

https://journals.sagepub.com/doi/pdf/10.1097/00004647-199601000-00005

Comparison of Methods for Analysis of Clinical [11C]Raclopride Studies

Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Ziprasidone Study Group.

Positron emission tomography (PET) and11C-raclopride were used to measure the occupancy of central dopamine D2 receptors by a new neuroleptic, CP-88,059-1. In a double blind dose escalation study, seven healthy male subjects received a predose of between 2 mg and 60 mg CP-88,059-1, 5 h before PET scanning. One additional subject was assigned to placebo predose. Receptor occupancy was defined as the percentage reduction in binding potential compared with that seen in the subject predosed with placebo and with that seen in seven unmedicated normal volunteers previously studied. Binding of11C-raclopride decreased in a dose dependent manner, and 85% dopamine D2 receptor occupancy was achieved with the highest dose of CP-88,059-1. The findings confirm that brain dopamine D2 receptors are blocked by CP-88,059-1 and suggest that an effective antipsychotic dose will be between 20 mg and 40 mg. The study highlights the potential of positron emission tomography in the preclinical evaluation of new drugs.

/pdf/dose-dependent-occupancy-of-central-dopamine-d2-receptors-by-16b5wt3f7r.pdf

Dose dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88,059-01: a study using positron emission tomography and 11C-raclopride.

M. Cuddigan

Papers

Dose dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88,059-01: a study using positron emission tomography and 11C-raclopride.