PET Quantification of 5-HT1A Receptor Binding

Following correction for tissue attenuation, PET scan of each patient was corrected for head motion, co-registered to the structural T1-weighted image. The latter was afterwards normalized to the Montreal Neurological Institute (MNI) space producing a transformation matrix that was further applied to normalize co-registered PET data to MNI space. All preprocessing steps were done using SPM (Wellcome Trust Centre for Neuroimaging, London, United Kingdom; http://www.fil.ion.ucl. ac.uk/spm/) and Matlab 2018a (The Mathworks Inc., Natick, MA, USA). Subsequently, time activity curves (TACs) were extracted for selected regions of interest (ROIs) - left and right DLPFC and cerebellar white matter (CWM). DLPFC ROIs were defined as a sphere with diameter of 10 mm around the MNI coordinate representing the individual application point of TBS treatment. The CWM ROI was extracted using an in-house created atlas [60 (link)]. To reduce the noise induced by short frames in the beginning of the scan, the first 2 min (frames 12 × 5 s and 6 × 10 s) of the measurement were resampled to 20-s frames.
The arterial input functions representing non-metabolized radioligand in plasma were obtained as product of the whole blood activity, plasma-to-whole blood ratio (average) and fraction of intact radioligand in the plasma (fitted with the Hill-type function). Afterwards, the specific volume of distribution (V_S), representing the amount of radioligand bound solely to the target 5-HT_1A receptor in the investigated target tissue, i.e. in DLPFC. Here, distribution volume V_S is equal to the binding potential (BP_P) of 5-HT_1A receptor as defined by Innis et al. 2007 [61 (link)]. Quantification of 5-HT_1A receptor V_S was carried out utilizing a constrained two-tissue compartment model. Here, CWM was fitted and the ratio of K₁/k₂ (K₁ - rate constant for transfer from arterial plasma to tissue, k₂ - rate constant for transfer from tissue to arterial plasma) was fixed for the DLPFC regions [62 ]. Model fitting and quantification of [carbonyl-¹¹C]WAY-100635 was carried out in PMOD 4.201 (PMOD Technologies Ltd., Zurich, Switzerland; www.pmod.com).