Comparison of two high affinity gallium-68-labeled bradykinin receptor antagonists for in vivo imaging of bradykinin B1 receptor expression
Bibliographic record
Abstract
113 Objectives The bradykinin B1 receptor (B1R) is a G protein-coupled receptor and is minimally expressed in normal tissues. Due to its overexpression in a variety of cancers, B1R is a promising cancer imaging biomarker. In this study, we synthesized and evaluated two B1R-targeting peptides, 68Ga-P05022 (68Ga-DOTA-Pip-B9858) and 68Ga-Z02176 (68Ga-DOTA-Pip-B9958), for imaging B1R expression with PET (Pip: 4-amino-(1-carboxymethyl)piperidine; B9858:Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic; B9958: Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg). Methods The DOTA-conjugated peptides were synthesized by solid phase peptide synthesis, and reacted with GaCl3 to obtain cold standards. B1R binding affinity was measured by in vitro competition binding assays. The peptides were labeled with 68Ga by microwave heating followed by HPLC purification. LogD7.4 values were determined via traditional shake flask method. PET/CT imaging and biodistribution studies were performed in NODSCID/IL2RKO mice bearing both B1R-negative (B1R-) HEK293T wild-type tumor and B1R-positive (B1R+) HEK293T::hB1R tumor. Blocking studies were performed by co-injecting the tracers with their respective cold standard (100 μg). Results P05022 and Z02176 were obtained with 12 % and 18 % overall yield. The binding affinities (Ki) of P05022 and Z02176 to hB1R were 5.5 ± 0.1 and 2.5 ± 0.8 nM, respectively. 68Ga-labeled P05022 and Z02176 were prepared in 42 - 76 % decay-corrected radiochemical yield, with > 99 % radiochemical purity and 41 - 282 GBq/μmol specific activity. Both tracers were highly hydrophilic with LogD7.4 of -2.65 ± 0.15 and -4.15 ± 0.04 for P05022 and Z02176, respectively. The PET imaging and biodistribution studies at 1-h post-injection showed extremely low background (~ 1 %ID/g or less) of both tracers. Only kidneys, bladder, and B1R+ tumor were clearly visualized in PET images. The biodistribution data showed that both tracers were excreted mainly via the renal pathway. At 1-h post-injection, B1R+ tumor uptake for 68Ga-Z02176 (28.9 ± 6.21 %ID/g) was higher than 68Ga-P05022 (11.6 ± 3.30 %ID/g). The B1R+ tumor-to-blood and B1R+ tumor-to-muscle ratios were also higher with 68Ga-Z02176 (56.1 ± 17.3 and 167 ± 57.6) compared to 68Ga-P05022 (34.3 ± 15.2 and 103 ± 30.2). Negligible uptake in B1R- tumors indicated that the uptake in B1R+ tumors was receptor mediated. In addition, co-injecting with the cold standard reduced B1R+ tumor uptake by more than 85 % for both radiotracers. Conclusions 68Ga-P05022, 68Ga-Z02176, and their cold compounds were successfully synthesized and characterized. Both tracers had high binding affinities for B1R. PET imaging and biodistribution studies revealed that 68Ga-Z02176 was superior to 68Ga-P05022 and other previously reported tracers for B1R-targeting imaging. Our results indicate that 68Ga-Z02176 warrants further studies for potential clinical translation.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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".