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

Molecular imaging, which can allow the non-invasive monitoring of biological processes in living subjects, has the potential to enhance understanding of disease and drug activity in both preclinical and clinical drug studies, aiding effective translational research. Gambhir and colleagues review the applications of molecular imaging in drug development, and discuss challenges that need to be addressed to optimize its utility.

Molecular imaging in drug development

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

Background:Al though the prin ci pal brain tar get that all an tipsy chotic drugs at tach to is the do pamine D2 re cep tor, tra di tional or typi cal an tipsy chot ics, by at tach ing to it, in duce ex tra py r a mi dal signs and symp toms (EPS). They also, by bind ing to the D2 re cep tor, ele vate se rum pro lac tin. Atypi cal a ntipsy chot ics given in dos ages within the clini cally ef fec tive range do not bring about these adverse clini cal ef fects. To un der stand how these drugs work, it is im por tant to ex am ine the atypical an tipsychot ics' mecha nism of ac tion and how it dif fers from that of the more typi cal drugs.Method:This re view analy zes the af fini ties, the oc cu pan cies, and the dis so cia tion time- course of vari ous an tipsy chot ics at do pa mine D2 re cep tors and at se ro tonin (5-HT) re cep tors, both in the test tube and in live pa tients.Results:Of the 31 an tipsy chot ics ex am ined, the older tra di tional an tipsy chot ics such as tri fluperazine, pi mozide, chlor ...

https://journals.sagepub.com/doi/pdf/10.1177/070674370204700106

Atypical Antipsychotics: Mechanism of Action:

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.

Positron emission tomography (PET) and11C-raclopride were used to assess the time course of binding to central dopamine D2 receptors by the novel neuroleptic ziprasidone. In a third party blind study, six healthy male control subjects received a predose of 40 mg ziprasidone and were scanned at an interval of between 4 and 36 h post-dose. One additional subject was assigned to placebo predose and was scanned at 4 h post-dose. Binding potential (BP) was compared with that seen in the subject predosed with placebo and with that seen in nine unmedicated normal volunteers. Subjects studied up to 12 h post-dose had BPs that were greater than 2 SD less than the mean BP, indicative of extensive D2 receptor binding by ziprasidone. With increasing time between dosing and PET scanning there was a curvilinear increase in BP, so that all studies performed at or after 18 h post-dose gave BPs in the normal range (mean±2 SD). Elevated prolactin levels returned to within the normal range by 18 h post-dose. PET measures of binding potential correlated significantly with serum levels of ziprasidone at the time of scanning and less significantly with absolute prolactin levels at the same time.

/pdf/the-time-course-of-binding-to-striatal-dopamine-d2-receptors-bhewgrlu00.pdf

S. J. Warrington

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.

The time course of binding to striatal dopamine D2 receptors by the neuroleptic ziprasidone (CP-88,059-01) determined by positron emission tomography