Summary
The therapeutic window for treatment of schizophrenia (SZ) with antipsychotics is limited. Excessive dosage
of antipsychotics may lead to dopamine supersensitivity psychosis (DSP), a condition when dopamine D2high
receptors (the active form of the D2 receptor) are upregulated in the mesolimbic system, in turn causing a
need to escalate antipsychotics dose to alleviate the symptoms. To avoid DSP, it is necessary to closely
monitor the changes in D2high. This can be accomplished using a specific D2high receptor agonist, visualized
through positron emission tomography (PET). We have synthesized MCL-524, a highly selective D2 agonist
which is characterized by sub-nanomolar binding affinity to D2high, minimal affinity to other D2-like receptors
or to other dopamine or non-dopamine receptor families, good metabolic stability, and good permeation
through the blood brain barrier. Preliminary data in rats indicate a good ADME profile, with high binding in
the D2-rich striatum, and low binding in other brain regions and peripheral organs. This ligand must be
rigorously and reproducibly characterized before it can be tested in humans. In aim 1, we will complete
preclinical experiments to ensure safety and reliability of MCL-524, including broad off-target binding, ADME
evaluation, and a 14-day toxicology study in rats. In aim 2, we will evaluate the test-retest variability and
biodistribution of [18F]MCL-524 in rhesus monkeys to increase rigor and reproducibility for clinical studies. In
aim 3, we will test in vivo selectivity of [18F]MCL-524 using specific antagonist for D2 (benperidol) and D3
(SB277011A) in PET imaging studies: first we will use micro-PET to assess binding and specificity of
[18F]MCL-524 in the presence and absence of benperidol or SB277011A in control and amphetamine
sensitized rats, an established model of up-regulated D2high receptors, in vivo. In a second approach, we will
test [18F]MCL-524 in analogous blocking studies in non-human primates (macaque monkeys) which are
physiologically closer to humans than rodents, using PET. In aim 4, we will perform studies to support an
investigational New Drug (IND) application, namely GMP synthesis and formulation in the CMC (chemistry,
manufacturing, and control) program to ensure a reproducible and validated method of radiolabeling and
dosage administration. Antipsychotics are the primary means of illness management in SZ, and a better
understanding of the etiology of DSP will allow us to avoid it in patients, improving their overall outcome. The
overarching goal is to develop MCL-524 as a PET radiotracer and a predictive biomarker of dopaminergic
treatment responses in SZ, to minimize the incidence of DSP. Ultimately, this tool will improve patient`s lives
and reduce the socioeconomic burden associated with schizophrenia.
