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![Synthesis of [¹⁸F]BMS-986229 (PD-L1 macrocyclic PET Ligand). Reagents and conditions: A [¹⁸F]KF, K.2.2.2, K2CO3,DMSO, 120 °C for 10 min B Sodium ascorbate, CuSO4, t-BuOH and water for 10 min](publication/376230440/figure/fig1/AS:11431281225049111@1708570373061/Synthesis-of-FBMS-986229-PD-L1-macrocyclic-PET-Ligand-Reagents-and-conditions-A.png)
Synthesis of [¹⁸F]BMS-986229 (PD-L1 macrocyclic PET Ligand). Reagents and conditions: A [¹⁸F]KF, K.2.2.2, K2CO3,DMSO, 120 °C for 10 min B Sodium ascorbate, CuSO4, t-BuOH and water for 10 min
Source publication
![Synthesis of [¹⁸F]BMS-986229 (PD-L1 macrocyclic PET Ligand). Reagents...](publication/376230440/figure/fig1/AS:11431281225049111@1708570373061/Synthesis-of-FBMS-986229-PD-L1-macrocyclic-PET-Ligand-Reagents-and-conditions-A_Q320.jpg)
A same-day PET imaging agent capable of measuring PD-L1 status in tumors is an important tool for optimizing PD-1 and PD-L1 treatments. Herein we describe the discovery and evaluation of a novel, fluorine-18 labeled macrocyclic peptide-based PET ligand for imaging PD-L1.
[18F]BMS-986229 was synthesized via copper mediated click-chemistry to yield a...
Citations
... 18 F-BMS-986192, which was evaluated in non-small cell lung cancer and melanoma, demonstrated a correlation with pathologic evaluation and responses using this method but was challenging to synthesize and was isolated in only modest radiochemical yields (13,14). 18 F-BMS-986229 is a macrocyclic peptide with high affinity for PD-L1, tight binding with a slow off-rate from the receptor, rapid clearance from non-PD-L1-expressing tissues, and the ability to be isolated in higher yields while also being less challenging to synthesize than 18 F-BMS-986192 (15,16). Preclinical evaluations of 18 F-BMS-986229 demonstrated specific binding to PD-L1-expressing tissues in vitro and in vivo (15,16). ...
... 18 F-BMS-986229 is a macrocyclic peptide with high affinity for PD-L1, tight binding with a slow off-rate from the receptor, rapid clearance from non-PD-L1-expressing tissues, and the ability to be isolated in higher yields while also being less challenging to synthesize than 18 F-BMS-986192 (15,16). Preclinical evaluations of 18 F-BMS-986229 demonstrated specific binding to PD-L1-expressing tissues in vitro and in vivo (15,16). We report what is, to our knowledge, the first study of the PD-L1-targeting radiotracer 18 F-BMS-986229 with PET imaging (PD-L1 PET) performed on patients with GEC and the first clinical use of 18 F-BMS-986229 as a PD-L1-targeting radiotracer. ...
... On the basis of the cocrystal structure of BMS-986189 and PD-L1, a propargyl glycine moiety was incorporated into the portion of the peptide that was solvent-exposed. This macrocyclic peptide was labeled with 18 F via a covalent bond by the use of the copper-catalyzed azide-alkyne cycloaddition reaction with a propargyl glycine on the peptide and an azide-containing 18 Fprosthetic group, 18 F-BMT-187144 (15). ...
Anti-programmed death 1 (PD-1) inhibitors are the standard of care for advanced gastroesophageal cancer. Although recommendations and approval by regulatory agencies are often based on programmed death ligand 1 (PD-L1) expression, pathologic assessments of PD-L1 status have several limitations. Single-site biopsies do not adequately capture disease heterogeneity within individual tumor lesions or among several lesions within the same patient, the PD-L1 combined positive score is a dynamic biomarker subject to evolution throughout a patient's disease course, and repeated biopsies are invasive and not always feasible. Methods: This was a prospective pilot study of the PD-L1-targeting radiotracer, 18F-BMS-986229, with PET imaging (PD-L1 PET) in patients with gastroesophageal cancer. Patients were administered the 18F-BMS-986229 radiotracer intravenously at a dose of 370 MBq over 1-2 min and underwent whole-body PET/CT imaging 60 min later. The primary objective of this study was to evaluate the safety and feasibility of 18F-BMS-986229. The trial is registered with ClinicalTrials.gov (NCT04161781). Results: Between February 3, 2020, and February 2, 2022, 10 patients with gastroesophageal adenocarcinoma underwent PD-L1 PET. There were no adverse events associated with the 18F-BMS-986229 tracer, and imaging did not result in treatment delays; the primary endpoint was achieved. Radiographic evaluation of PD-L1 expression was concordant with pathologic assessment in 88% of biopsied lesions, and 18F-BMS-986229 uptake on PET imaging correlated with pathologic evaluation by the combined positive score (Spearman rank correlation coefficient, 0.64). Seventy-one percent of patients with 18F-BMS-986229 accumulation on PET imaging also had lesions without 18F-BMS-986229 uptake, highlighting the intrapatient heterogeneity of PD-L1 expression. Patients treated with frontline programmed death 1 inhibitors who had 18F-BMS-986229 accumulation in any lesions on PET imaging had longer progression-free survival than patients without tracer accumulation in any lesions (median progression-free survival, 28.4 vs. 9.9 mo), though the small sample size prevents any definitive conclusions. Conclusion: PD-L1 PET imaging was safe, feasible, and concordant with pathologic evaluation and offers a potential noninvasive tool to assess PD-L1 expression.
... The development of a same-day PET imaging agent capable of measuring PD-L1 status in tumors holds significant importance for optimizing PD-1 and PD-L1 treatments. In a recent issue of the European Journal of Nuclear Medicine and Molecular Imaging (EJNMMI), Dr. Donnelly and colleagues from Small Molecule Drug Discovery-PET Radiochemical Synthesis, Bristol Myers Squibb Research and Early Development, USA, present a meticulously designed and executed study on the discovery and evaluation of a novel fluorine-18 labeled macrocyclic peptide-based PET ligand, [ 18 F]BMS-986229, for imaging PD-L1 [30]. This ligand was designed based on BMS986189, a potent macrocyclic peptide-derived PD-L1 antagonist with picomolar PD-L1 affinity. ...
... When comparing the biodistribution characteristics of [ 18 F]F-BMS-986229 is a macrocyclic peptide ligand specifically designed to target PD-L1 [26]. Macrocyclic peptides offer improved stability and binding affinity compared to linear peptides, thereby highlighting their suitability as PET imaging agents [27,28]. Although [ 18 F]BMS-986192 proves valuable in clinical settings, its synthesis remains challenging, resulting in the isolation of the ligand in modest yields [28]. ...
... Macrocyclic peptides offer improved stability and binding affinity compared to linear peptides, thereby highlighting their suitability as PET imaging agents [27,28]. Although [ 18 F]BMS-986192 proves valuable in clinical settings, its synthesis remains challenging, resulting in the isolation of the ligand in modest yields [28]. Technical hurdles stemming from the complex synthesis process and the requirement for high radiochemical purity constrain the widespread adoption and clinical utility of [ 18 F]BMS-986192. ...
... The synthesis of 18 F-BMS-986229 has been described in recent published paper [19]. Summarized here, 18 F-BMS-986229 was prepared via a copper-mediated azide-alkyne cycloaddition reaction between 18 F-BMT-187144, a novel azide containing prosthetic group discovered at Bristol Myers Squibb, and an advanced alkyne containing macrocyclic peptide, a process that proceeded in high radiochemical yield (17% non-decay corrected yield), high chemical and radiochemical purity (> 90%) with high molar activity (229.4 ...
... According to the preclinical results reported herein, 18 [19]. Furthermore, 18 F-BMS-986229 demonstrates the advantages of a shorter in vivo half-life and a lower molecular weight PET tracer, compared to antibody-based PD-L1 PET tracers. ...
... In vivo PET imaging of tumor-bearing mice shows that tracer uptake was clearly higher in PD-L1 positive tumors compared to PD-L1 negative tumors (5:1 ratio), indicating the tracer's PD-L1 binding specificity. As reported in another paper [19], 18 F-BMS-986229 was synthesized via copper-mediated click chemistry to create a PD-L1 PET tracer with picomolar affinity suitable for evaluating PD-L1 expression. This paper also demonstrates, via PET imaging in healthy NHPs, that the same advantages of macrocyclic peptide PET tracers in producing high signalto-noise in PD-L1 positive tissue and low background signal in non-expressing tissue, which is validated by comparing with 89 Zr-radiolabeled PD-L1 Adnectin or mAb PET tracers. ...
Purpose
In cancer immunotherapy, the blockade of the interaction between programmed death-1 and its ligand (PD-1:PD-L1) has proven to be one of the most promising strategies. However, as mechanisms of resistance to PD-1/PD-L1 inhibition include variability in tumor cell PD-L1 expression in addition to standard tumor biopsy PD-L1 immunohistochemistry (IHC), a comprehensive and quantitative approach for measuring PD-L1 expression is required. Herein, we report the development and characterization of an ¹⁸ F-PD-L1-binding macrocyclic peptide as a PET tracer for the comprehensive evaluation of tumor PD-L1 expression in cancer patients.
Procedures
¹⁸ F-BMS-986229 was characterized for PD-L1 expression assessment by autoradiography or PET imaging. ¹⁸ F-BMS-986229 was utilized to evaluate tumor PD-L1 target engagement in competition with a macrocyclic peptide inhibitor of PD-L1 (BMS-986189) over a range of doses using PET imaging. A whole-body radiation dosimetry study of ¹⁸ F-BMS-986229 in healthy non-human primates (NHPs) was performed.
Results
In vitro autoradiography showed an 8:1 binding ratio in L2987(PD-L1 +) vs. HT-29 (PD-L1-) tumors, more than 90% of which could be blocked with 1 nM of BMS-986189. Ex vivo autoradiography showed that ¹⁸ F-BMS-986229 detection was penetrant over a series of sections spanning the entire L2987 tumor. In vivo PET imaging in mice demonstrated a 5:1 tracer uptake ratio (at 90–100 min after tracer administration) in L2987 vs. HT-29 tumors and demonstrated 83%-93% specific binding of BMS-986189 within those dose ranges. In a healthy NHP dosimetry study, the resultant whole-body effective dose was 0.025 mSv/MBq.
Conclusion
¹⁸ F-BMS-986229 has been preclinically characterized and exhibits high target specificity, low background uptake, and a short blood half-life supportive of same day imaging in the clinic. As the PET tracer, ¹⁸ F-BMS-986229 shows promise in the quantification of PD-L1 expression, and its use in monitoring longitudinal changes in patients may provide insights into PD-1:PD-L1 immuno-therapy treatment outcomes.
