The construction of potent peptide probes for selectively detecting denatured collagen is crucial for a variety of widespread diseases. However, all of the denatured collagen-targeting peptide probes found till date primarily utilized the repetitive (Gly-X-Y)n sequences with exclusively imino acids Pro and Hyp in the X and Y positions, which stabilized the triple helical conformation of the peptide probes, resulting in severe obstacles for their clinical applications. A novel series of peptide probes have been constructed by incorporating nonimino acids at the X position of the (GPO)3GXO(GPO)4 sequence, while the X-site residue is varied as Tyr, Phe, Asp, and Ala, respectively. Peptide probes FAM-GYO and FAM-GFO containing aromatic residues Tyr and Phe at the X position showed similarly high binding affinity and tissue-staining efficacy as the well-established peptide probe FAM-GPO, while peptide probes FAM-GDO and FAM-GAO with the corresponding charged residue Asp and the hydrophobic residue Ala indicated much weaker binding affinity and tissue-staining capability. Furthermore, FAM-GYO and FAM-GFO could specifically detect denatured collagen in different types of mouse connective tissues and efficiently stain various human pathological tissues. We have revealed for the first time that the incorporation of nonimino acids, particularly aromatic residues at the X and Y positions of the repetitive (Gly-X-Y)n sequences, may provide a convenient strategy to create novel robust collagen-targeting peptide probes, which have promising diagnostic applications in collagen-involved diseases.
To verify its application potential in the field of cardiac and cerebral disease diagnosis, the first human experiment of [18F]BIBD-239 was reported. Synthesized via a GMP-compliant automated process on a CFN-MPS200 synthesizer (per Chinese Pharmacopoeia 2020), it achieved radiochemical purity >95%, nondecay-corrected yield >15%, and molar activity >120 GBq/μmol (total synthesis time 80 ± 5 min) under optimized conditions (95 °C, 10 min). Preclinical studies in rats confirmed TSPO-specific binding. First-in-human studies (6 healthy volunteers, 1 high-grade glioma (HGG), 1 low-grade glioma (LGG)) showed it rapidly crossed the blood–brain barrier with low normal brain retention and high sustained myocardial uptake without in vivo defluorination. HGG had higher tumor-to-background ratios (3.09) than LGG (2.33), with uptake beyond MRI-enhanced regions, correlating with histopathology. The whole-body effective dose (0.0145 ± 0.0018 mSv/MBq) was lower than [18F]FDG. [18F]BIBD-239 has robust synthesis, favorable pharmacokinetics, and TSPO-specific binding, enabling dual utility in noninvasive glioma grading and glucose-independent myocardial imaging, supporting translation in neuro-oncology and cardiovascular assessment.
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