Assessment of [11C]ER176 to Image Translocator Protein in Brain and Whole Body of Healthy People

Objective

Translocator protein 18 kDa (TSPO) is highly expressed in activated microglia and reactive astrocytes in brain, and it may, thereby, be a useful biomarker of neuroinflammation. We developed [(11)C]PBR28 as a positron emission tomographic (PET) radioligand to bind to TSPO and measure its density. Although [(11)C]PBR28 has high in vivo specific signal, it is very sensitive to the high and low affinity states of TSPO, which are caused by the rs6971 single nucleotide polymorphism (SNP) in the fourth exon of the TSPO gene resulting in a nonconservative alanine-to-threonine substitution in position 147 of the encoded TSPO protein. This co-dominant mutation yields three genetic groups: HH, HL, and LL, where H is the high-affinity form and L is the low affinity form. The frequency of the L allele is approximately 30%; thus, the frequency of the LL homozygote is approximately 9%. The affinity of PBR28 to H and L forms differs about 50 fold; thus, LL carriers provide no measureable signal in brain from [(11)C]PBR28. We recently developed a new TSPO ligand ER176, the affinity of which differs by only 1.2 fold and therefore LL carriers should provide measureable brain uptake. The purpose of this study is to assess the potential of [(11)C]ER176 to image TSPO in brain, characterize its binding sensitivity in lung of healthy subjects from all three genetic groups, and to do whole-body imaging for biodistribution and estimation of radiation dosimetry in humans.

The present protocol will use a new PET ligand [(11)C]ER176 to 1) perform an initial whole-body scan after [(11)C]ER176 injection in a single healthy volunteer to confirm wide-spread distribution of radioactivity to different body organs (Phase 0); 2) perform kinetic brain scans in healthy volunteers of 3 different genotypes, with about half of these volunteers undergoing lung scans in the same session (Phase 1), and; 3) perform whole-body imaging in healthy volunteers (Phase 2).

This study will assess the relative robustness of absolute quantitation of TSPO in the brain of healthy subjects, using an arterial input function and pharmacokinetic modeling. In addition, lung imaging will provide in vivo binding sensitivity of [(11)C]ER176 to TSPO genotype. Furthermore, the whole-body imaging would estimate the radiation-absorbed doses for future use of [(11)C]ER176 in clinical studies.

Study Population

We will select up to 36 healthy adult female and male volunteers (age 18 and older) of 3 different TSPO genotypes for brain imaging, and up to 11 additional healthy volunteers for whole body dosimetry analysis.

Design

For absolute quantification of TSPO, up to 36 healthy controls (up to 12 each of three TSPO genotypes) will have brain PET imaging using [(11)C]ER176 and these subjects will have the arterial line and a brain MRI scan. In about half of those subjects from each genotype group, lungs will be scanned in the same session. For radiation dosimetry of [(11)C]ER176, up to 11 subjects will have whole-body PET imaging. These subjects will not have arterial line and MRI scans.

Outcome Measures

The primary outcome measures are: (a) To assess absolute quantitation of TSPO with [(11)C]ER176, we will determine the identifiability and time stability of distribution volume in the brain calculated with compartmental modeling. The difference in mean distribution volumes among subjects with different genotypes would be used to evaluate the genotype sensitivity of [(11)C]ER176. (b) To assess whole-body biodistribution and dosimetry of [(11)C]ER176 we will use the organ time-activity curves.

As secondary outcome measure, we will examine the effect of polymorphism on [(11)C]ER176 binding in lungs because lungs have much higher density of TSPO and may be more effective to show whether ER176 is sensitive to the SNP.