Towards In Vivo Proof-of-Binding of 18F-labeled Inhibitor [18F]TRACK to Peripheral Tropomyosin Receptor Kinases
Bibliographic record
Abstract
Abstract Background Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are a family of tyrosine kinases primarily expressed in neuronal cells of the brain. Identification of oncogenic alterations in Trk expression as a driver in multiple tumor types has increased interest in their role in human cancers. Recently, first and second generation 11 C and 18 F-labeled Trk inhibitors e.g.[ 18 F]TRACK have been developed. The goal of the present study was to analyze the direct interaction of [ 18 F]TRACK with peripheral Trk receptors in vivo to prove its specificity for use as a functional imaging probe. Methods In vitro uptake and competition experiments were carried out using the colorectal cancer cell line KM12. Dynamic PET experiments were performed with [ 18 F]TRACK, either alone or in the presence of amitriptyline, an activator of Trk, entrectinib, a Trk inhibitor, or unlabeled reference compound TRACK in KM12 tumor bearing athymic nude mice as well as B6129SF2/J and corresponding B6;129S2- Ntrk2 tm1Bbd /J mice. Western blot and immunohistochemistry experiments were done with KM12 tumors, brown adipose tissue (BAT), and brain tissue samples. Results Uptake of [18F]TRACK was increasing over time reaching 208 ± 72% radioactivity per mg protein (n = 6/2) after 60 min incubation time. Entrectinib and TRACK competitively blocked [ 18 F]TRACK uptake in vitro (IC 50 30.9 ± 3.6 and 29.4 ± 9.4nM; both n = 6/2). [ 18 F]TRACK showed uptake into KM12 tumors (SUV mean,60min 0.43 ± 0.03; n = 6). Tumor-to-muscle ratio reached 0.9 (60min) and 1.2 (120min). In TrkB expressing BAT [ 18 F]TRACK uptake reached SUV mean,60min 1.32 ± 0.08 (n = 7). Activation of Trk through amitriptyline resulted in a significant increase of KM12 tumor uptake 23% (SUV mean,60min from 0.53 ± 0.01 to 0.43 ± 0.03; n = 6; p < 0.05) and in BAT 21% (SUV mean,60min from 1.32 ± 0.08; n = 5 to 1.59 ± 0.07; n = 6; p < 0.05). Immunohistochemistry showed TrkB > TrkA expression on BAT fat cells, but TrkA > TrkB in whole brain. WB analysis showed 7-fold higher TrkB expression in BAT versus KM12 tumor tissue. Conclusion The present data shows that radiotracer [ 18 F]TRACK can target peripheral Trk receptors in human KM12 colon cancer as well as brown adipose tissue as confirmed through in vitro and in vivo blocking experiments. Higher TrkB versus TrkA protein expression was detected in brown adipose tissue of mice confirming a peripheral functional role of brain-derived neurotrophic factor in adipose tissue.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.003 |
| Research integrity | 0.000 | 0.001 |
| 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 teacher head, 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".