Blocking of efflux transporters in rats improves translational validation of brain radioligands.

Background: Positron emission tomography (PET) is a molecular imaging technique that can be used to investigate the in vivo pharmacology of drugs. Initial preclinical evaluation of PET tracers is often conducted in rodents due to the accessibility of disease models as well as economic considerations. Compared to larger species, rodents display a higher expression and/or activity of efflux transporters such as the P-glycoprotein (P-gp).

Radiosynthesis and preclinical evaluation of [ C]Cimbi-701 - Towards the imaging of cerebral 5-HT receptors.

The serotonin 7 (5-HT ) receptor is suggested to be involved in a broad variety of CNS disorders, but very few in vivo tools exist to study this important target. Molecular imaging with positron emission tomography (PET) would enable an in vivo characterization of the 5-HT receptor. However, no clinical PET radiotracer exists for this receptor, and thus we aimed to develop such a tracer.

Towards selective CNS PET imaging of the 5-HT receptor system: Past, present and future.

Since its discovery in 1993, the serotonin receptor subtype 7 (5-HT) has attracted significant attention as a potential drug target; due to its elucidated roles in conditions such as insomnia, schizophrenia, and more. Therefore, it is unsurprising that there has been relatively early efforts undertaken to develop a positron emission tomography (PET) imaging agent for said receptor system. PET can be clinically used to probe receptor systems in vivo, permitting information such as a drug's occupancy against this system to be investigated.

The Chemogenetic Receptor Ligand Clozapine N-Oxide Induces Neuroreceptor Occupancy and Reduces Striatal Glutamate Levels.

Chemogenetic studies with the ligand clozapine N-oxide (CNO) are predicated upon the assumption that CNO is devoid of actions at natural neuroreceptors. However, recent evidence shows that CNO may be converted back to clozapine (CLZ) , which could yield plasma concentrations that may be sufficient to occupy inter alia dopamine D and serotonin 5HT receptors in living brain. To test this phenomenon, we measured striatal dopamine D receptor occupancy with [F]fallypride PET and serotonin 5HT occupancy using [F]MH.

Development and Evaluation of Two Potential 5-HT Receptor PET Tracers: [F]ENL09 and [F]ENL10.

The latest addition to the serotonin (5-HT) receptor family is the 5-HT receptor (5-HTR). This receptor has gained interest as a drug target due to its involvement in various disorders such as depression or schizophrenia. There is currently no clinically validated positron emission tomography (PET) tracer for the 5-HTR available.

Synthesis, radiofluorination, and preliminary evaluation of the potential 5-HT receptor agonists [ F]Cimbi-92 and [ F]Cimbi-150.

An agonist PET tracer is of key interest for the imaging of the 5-HT receptor, as exemplified by the previously reported success of [ C]Cimbi-36. Fluorine-18 holds several advantages over carbon-11, making it the radionuclide of choice for clinical purposes. In this respect, an F-labelled agonist 5-HT receptor (5-HT R) tracer is highly sought after.