The PET Radioligand 18F-FIMX Images and Quantifies Metabotropic Glutamate Receptor 1 in Proportion to the Regional Density of Its Gene Transcript in Human Brain

Abstract

A recent study from our laboratory found that (18)F-FIMX is an excellent PET radioligand for quantifying metabotropic glutamate receptor 1 (mGluR1) in monkey brain. This study evaluated the ability of (18)F-FIMX to quantify mGluR1 in humans. A second goal was to use the relative density of mGluR1 gene transcripts in brain regions to estimate specific uptake and nondisplaceable uptake (VND) in each brain region.

Methods: After injection of 189 ± 3 MBq of (18)F-FIMX, 12 healthy volunteers underwent a dynamic PET scan over 120 min. For 6 volunteers, images were acquired until 210 min. A metabolite-corrected arterial input function was measured from the radial artery. Four other subjects underwent whole-body scanning to estimate radiation exposure.

Results: (18)F-FIMX uptake into the human brain was high (SUV = 4-6 in the cerebellum), peaked at about 10 min, and washed out rapidly. An unconstrained 2-tissue-compartment model fitted the data well, and distribution volume (VT) (mL⋅cm(-3)) values ranged from 1.5 in the caudate to 11 in the cerebellum. A 120-min scan provided stable VT values in all regions except the cerebellum, for which an acquisition time of at least 170 min was necessary. VT values in brain regions correlated well with mGluR1 transcript density, and the correlation suggested that VND of (18)F-FIMX was quite low (0.5 mL⋅cm(-3)). This measure of VND in humans was similar to that from a receptor blocking study in monkeys, after correcting for differences in plasma protein binding. Similar to other (18)F-labeled ligands, the effective dose was about 23 μSv/MBq.

Conclusion: (18)F-FIMX can quantify mGluR1 in the human brain with a 120- to 170-min scan. Correlation of brain uptake with the relative density of mGluR1 transcript allows specific receptor binding of a radioligand to be quantified without injecting pharmacologic doses of a blocking agent.

Trial registration: ClinicalTrials.gov NCT02230592.

Keywords: 18F-FIMX; PET; gene transcripts; mGluR1.

Conflict of interest statement

DISCLOSURE

No other potential conflict of interest relevant to this article was reported.

© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Figures

FIGURE 1

(A) Metabolite-corrected arterial input function acquired over 120 min in a representative subject, fitted with a triexponential function. (B) Time–activity curves of brain regions of a subject fitted with 2-tissue-compartment model. Cerebellum (○) had highest uptake, thalamus (□) had intermediate uptake, and caudate nucleus (●) had lowest uptake.

FIGURE 2

Time–stability analysis. VT results are normalized to 2-tissue-compartment model/VT values measured at 120 min (n = 12) (A) and 210 min (n = 6) (B). ● = cerebellum and ○ = average of other brain regions. Although good stability was reached by 120 min in low-uptake regions of brain, cerebellum still showed upward trend at 120 min and eventually almost stabilized by 170 min. Higher SD bars after 160 min denote presence of subjects with aberrant VT values.

FIGURE 3

Parametric images in a representative subject. (A) MRI. (B) Logan. (C) Standard SA. (D) RSSA. Images obtained with Ichise’s multi-linear analysis 1 (MA1) and Zhou’s RE-GP are visually indistinguishable from Logan images and are not shown. Parametric maps obtained with SA (C) contained many failed voxels randomly scattered across the whole brain. RSSA (D) yielded maps of good quality, but VT values were severely underestimated compared with 2-tissue-compartment model.

FIGURE 4

Linear regression analysis between mRNA expression values measured by mRNA probe B for mGluR1 gene and average 2-tissue-compartment model/VT values of 18F-FIMX. VT of cerebellum, right-most data point, was calculated from 210 min of image acquisition. Linear regression shown in this graph, which includes cerebellum, has R2 of 0.992 and x-intercept of 0.5 mL·cm−3, which corresponds to VND of 18F-FIMX. When cerebellum is removed, R2 becomes 0.648 and x-intercept decreases to 0.3 mL·cm−3.