Effects of linker modifications on tumor-to-kidney contrast of 68Ga-PSMA imaging radioligands
Bibliographic record
Abstract
1142 Objectives: A number of 18F- and 68Ga-labeled radioligands targeting the prostate specific membrane antigen (PSMA) are used in the clinic to detect prostate cancer and metastases. Of these, 68Ga-PSMA-11 is the most widely used. However, the high uptake of 68Ga-PSMA-11 in kidneys can create halo-artifacts resulting in lower detection sensitivity for lesions between the kidneys. In this study we developed two 68Ga-labeled PSMA-targeting tracers based on 68Ga-PSMA-617 with the goal of improving tumor-kidney contrast compared to 68Ga-PSMA-11. Methods: PSMA-617, HTK01166 and HTK01167 were prepared on solid phase, while PSMA-11 was purchased commercially. In the structure of HTK01166 and HTK01167, the 2-naphthylalanine (2-Nal) in PSMA-617 was replaced with 2-indanylglycine (Igl) and 3,3-diphenylalanine (Dip), respectively. Cold standards were prepared and their binding affinity to PSMA was determined by in vitro competition assays. 68Ga labeling was performed in HEPES buffer (2 M, pH 5.0) with microwave heating for 1 min followed by HPLC purification. The stability of 68Ga-labeled PSMA-617, HTK01166 and HTK01167 was assessed in mouse plasma and monitored by HPLC. PET imaging and biodistribution studies were performed in mice bearing PSMA-expressing LNCap prostate cancer xenografts. Blocking studies were conducted with co-injection of DCFPyL (0.5 mg) for 68Ga-HTK01166 and 68Ga-HTK01167. Results: PSMA-617, HTK01166 and HTK01167 were synthesized in 25-39% yield and their cold Ga-complexed standards were obtained in 54-73% yield. 68Ga-labeled PSMA-11, PSMA-617, HTK01166 and HTK01167 were obtained in 46-71% average decay-corrected radiochemical yield with >99% radiochemical purity and 63-152 GBq/μmol average specific activity. 68Ga-labeled PSMA-617, HTK01166 and HTK01167 were relatively stable in mouse plasma with 90% uptake of 68Ga-HTK01166 and 68Ga-HTK01167 in LNCaP tumor xenografts at 1h pi, demonstrating their specificity for PSMA. CONCLUSION: Compared with 68Ga-PSMA-617, 68Ga-HTK01166 showed comparable PSMA binding affinity and tumor uptake, and almost 5-fold higher kidney uptake; whereas 68Ga-HTK01167 exhibited lower PSMA binding affinity, tumor uptake and kidney uptake. Compared with 68Ga-PSMA-11, 68Ga-HTK01167 had similar tumor uptake and tumor-to-blood contrast (23.8 ± 6.71 vs 20.4 ± 4.98) but higher tumor-to-muscle contrast (16.0 ± 3.79 vs 54.3 ± 16.1) and much lower kidney uptake.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 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 | 0.000 | 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".