Reduction in 5HT2A binding potential using [11C] MDL 100907 in schizophrenia

Background and Aims: Schizophrenia has been associated not only with altered dopamine receptors but also serotonin because of the possibility of serotonin's relationship in the therapeutic action of atypical antipsychotics. Some previous PET studies in drug naive patients using [18F]setoperone or in subjects at enhanced risk for schizophrenia using [18F]altanserin have demonstrated reductions in 5HT2A receptors in frontal and pre-frontal cortex, respectively. We now present the results of a study in drug free schizophrenia patients using the selective 5HT2A PET radioligand [11C] MDL 100907 (MDL). Methods: Ten medically healthy subjects with schizophrenia or schizoaffective disorder (SS) (9 males, 1 female, average age 41 + 9) and nine healthy normal controls (CS) (4 females, 5 males average age 32 + 8) were studied. Exclusion criteria for the schizophrenia population included any other DSM-IV Axis I diagnosis other than schizophrenia/schizoaffective disorder, evidence of a current acute psychotic episode or any neurological disorders. The schizophrenia population was given a washout period of 2-3 weeks from any neuroleptic medication and any medication with a known effect on serotonin receptors. In order to obtain measurements of 5-HT2A receptor levels, we administered 18-20 mCi IV bolus of the radiotracer [11C]MDL 100907 (MDL) followed by a 95-min PET scan. A parametric imaging approach (Zhou et al, 2003) was used to estimate MDL binding potential (BP) Results: When the 10 SS were compared with the nine healthy CS, we found that SS had lower 5HT2A binding potential (BP) by up to 50% in all cortical regions as compared to CS (p = 0.001). However, since several studies have shown an age-related decrease in 5HT2A receptor levels (Adams, et al, 2004), we also examined an age-matched subset of the population, which included 6 patients and 6 controls, matched to an average age of 33 +7 years for both populations. In the age matched set, SS had significantly lower BP than CS in the following regions: cingulate cortex (p= 0.02), orbito-frontal cortex (p= 0.04), pre-frontal cortex (p=0.02), and temporal cortex (p=0.03). Prior exposure to neuroleptics and other serotonin-affecting medications, though terminated at least two weeks before the PET study in this case, may have been a confound. However, when we grouped the subjects based on drug free period and dose of antipsychotics taken and analyzed the BP data in terms of these groups, we could find no significant relationship between drug free period or type and dose of antipsychotics and BP, using both parametric and non-parametric (rank-order) analyses. Conclusions: This study showed significant reductions in BP with MDL in cingulate, orbito-frontal, pre-frontal and temporal cortices, matching findings from previous PET studies of 5HT2A binding with PET as well as post-mortem studies (Meltzer, et al, 1999; Adams, et al, 2004). In addition, we show additional cortical regions that were not observed in those studies, which focused only on the frontal and pre-frontal cortices. In summary MDL is a suitable approach and practical for not only investigating the pathophysiology of schizophrenia, but providing a convenient short-lived selective radiotracer for drug development studies.