Test–retest reproducibility of [11C]PBR28 binding to TSPO in healthy control subjects

Abstract

Here, we examined reproducibility of [ 11 C]PBR28 binding in healthy subjects as quantified on a regional and voxel-by-voxel basis. In addition, a preliminary analysis of diurnal changes in TSPO availability was performed. MethodsTwelve subjects were examined with HRRT PET and [ 11 C]PBR28, six in the morning and afternoon on the same day, and six in the morning of two separate days. Regional Volume of distribution (V T ) values were derived using a region-of-interest based two-tissue compartmental analysis (2TCM), as well as a parametric approach. Metabolite-corrected arterial plasma was used as input function. ResultsFor the whole sample, the mean absolute variability of V T in gray matter (GM) was 18.3 ± 12.7 %. Intraclass Correlation Coefficient values in GM regions ranged from 0.90 to 0.94. Reducing the time of analysis from 91 to 63 minutes yielded a variability of 16.9 ± 14.9%. There was a strong correlation between the parametric and 2TCM-derived GM values (r=0.99). A significant increase in GM V T was observed between morning and afternoon examinations when using secondary methods of quantification (p=0.028). For the subjects examined at the same time of the day, the absolute variability was 15.9 ± 12.2 % for the 91 minute 2TCM data. [15,16], the study was designed so that six subjects were examined in the morning and afternoon on the same day, and six subjects at the same time point on two different days. Conclusions Methods SubjectsThe study was conducted at the Karolinska University Hospital, Solna, Sweden and was approved by the regional Ethics Committee in Stockholm and the Radiation Safety Committee at the Karolinska University Hospital, Stockholm.Subjects were recruited by advertisement and provided written informed consent. They were healthy according to medical history, clinical examination and routine laboratory tests in blood and urine. All subjects were assessed by a senior psychiatrist (K.C.), using the Mini International Neuropsychiatric Interview (MINI) for psychiatric diagnoses. None of the subjects had previously been exposed to psychopharmacological medication. Furthermore, a negative illegal drug screening test was ascertained in all subjects, prior to PET examination. None of the subjects were on any medication at the time of the study. No brain abnormality was detected on magnetic resonance imaging (MRI), as evaluated by a neuroradiologist at the MR-centre, Karolinska University Hospital, Solna.As demonstrated both in vitro and in vivo, [ 11 C]PBR28 binding is influenced by an identified single point mutation in the TSPO gene [8,17]. At screening, a blood sample was collected and genotyping was performed according to the description below. In total, 15 subjects were recruited. Of these, one was a low affinity binder (LAB) and was therefore excluded from the analysis. Two additional subjects were excluded due to technical issues with the PET measurements. The remaining twelve subjects were six men and six women, with a mean age of 23.9 SD ± 3.1 years. Six were high affinity binders ...

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“…[30][31][32] The average radioactivity administered was 435 6 50MBq (mean 6 standard deviation [SD]), with a specific radioactivity of 229 6 82GBq/mmol and an injected mass of 0.77 6 0.38 mg. PET data were acquired for 63 minutes. Arterial blood was sampled using an automated system for the first 5 minutes.…”

“…Arterial blood was sampled using an automated system for the first 5 minutes. Manual samples were drawn at 2, 4,6,8,10,15,20,25,30,45, and 60 minutes. All patients were genotyped for the genetic polymorphism of rs6971, which affects binding of TSPO radioligands, including [ 11 C]PBR28, both in vitro and in vivo.…”

“…All patients were genotyped for the genetic polymorphism of rs6971, which affects binding of TSPO radioligands, including [ 11 C]PBR28, both in vitro and in vivo. 30,33,34 Six of the subjects were high-affinity binders, and there was 1 mixed-affinity binder, whereas for 1 subject the genotype could not be determined. …”

“…30,33,34 Six of the subjects were high-affinity binders, and there was 1 mixed-affinity binder, whereas for 1 subject the genotype could not be determined.…”

“…WAPI analysis of TSPO binding has previously been shown to be sensitive to within-subject changes in V T , 37 and data based on 63-minute acquisition have shown similar reliability compared to longer timeframes. 30 To assess individual rate constants of K 1 , k 2 , k 3 , and k 4 , an additional analysis was performed using the 2-tissue compartment model (2TCM). …”