In Vivo Measurement of the Affinity and Density of Metabotropic Glutamate Receptor Subtype 1 in Rat Brain Using <sup>18</sup>F-FITM in Small-Animal PET
Bibliographic record
Abstract
UNLABELLED: Metabotropic glutamate receptor subtype 1 (mGluR1) is a crucial molecular target in the central nervous system disorders. 4-(18)F-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ((18)F-FITM) has been recently developed as a useful PET ligand for mGluR1 imaging in our laboratory. In this study, we aimed to measure the affinity and density of mGluR1 using PET with (18)F-FITM in rat brain under the in vivo conditions. METHODS: Binding potentials (BP(ND)) and amounts of specific binding (bound ligand concentration) at equilibrium state in brain regions were noninvasively estimated using the equilibrium analysis combined with the receptor-blocked approach (EA RBA) for kinetic analysis of (18)F-FITM PET results in place of reference tissue methods. Using BP(ND) and specific binding values of rats treated with multidose ligand, we performed Scatchard analyses for in vivo measurements of mGluR1 density (maximum number of binding sites, or B(max)) and ligand affinity (dissociation constant, or K(d)) in brain regions, respectively. RESULTS: The pretreatment of rats with unlabeled FITM (1 mg/kg) occupied an mGluR1 binding site of (18)F-FITM by more than 99% and did not affect the input function. Hence, we used the tissue time-activity curve for receptor-blocked rats as representative of the nondisplaceable (free and nonspecific binding of radioligand) compartment. The BP(ND) based on EA RBA showed a high correlation with the BP(ND) based on invasive Logan plot graphical analysis in the thalamus, hippocampus, striatum, and cingulate cortex. The K(d) (nM) and B(max) (pmol/mL) obtained by the Scatchard analyses with the multidose ligand assays were 2.1 and 36.3, respectively, for the thalamus; 2.1 and 27.5, respectively, for the hippocampus; 1.5 and 22.2, respectively, for the striatum; and 1.5 and 20.5, respectively, for the cingulate cortex with a high confidence. CONCLUSION: Our study is the first to our knowledge to measure the in vivo affinity (K(d) and binding potential) of (18)F-FITM and mGluR1 density (B(max)) with a high correlation to in vitro values in rat brain regions. This measurement using PET with (18)F-FITM would be a useful index for research about mGluR1 functions in central nervous system disorders and development of new pharmaceuticals.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".