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| Home > Publications database > Rational Linker Design to Accelerate Excretion and Reduce Background Uptake of Peptidomimetic PSMA-Targeting Hybrid Molecules. > print |
| 001 | 168092 | ||
| 005 | 20240229133557.0 | ||
| 024 | 7 | _ | |a 10.2967/jnumed.120.248443 |2 doi |
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| 024 | 7 | _ | |a 2159-662X |2 ISSN |
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| 037 | _ | _ | |a DKFZ-2021-00680 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Eder, Ann-Christin |0 P:(DE-He78)584449af653618bdd9539e668604ad74 |b 0 |
| 245 | _ | _ | |a Rational Linker Design to Accelerate Excretion and Reduce Background Uptake of Peptidomimetic PSMA-Targeting Hybrid Molecules. |
| 260 | _ | _ | |a New York, NY |c 2021 |b Soc. |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1647441601_32759 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 500 | _ | _ | |a 2021 Oct;62(10):1461-1467 |
| 520 | _ | _ | |a The evolution of peptidomimetic hybrid molecules for preoperative imaging and guided surgery targeting the prostate-specific membrane antigen (PSMA) significantly progressed over the past years and some approaches are currently evaluated for further clinical translation. However, accumulation in non-malignant tissue such as kidney, bladder, spleen or liver might limit tumor-to-background contrast for precise lesion delineation particularly in a surgical setting. To overcome these limitations a rational linker design aims at the development of a second generation of PSMA-11 based hybrid molecules with enhanced pharmacokinetic profile and improved imaging contrasts. Methods: A selection of rational designed linkers was introduced to the PSMA-targeting hybrid molecule Glu-urea-Lys-HBED-CC-IRDye800CW resulting in a second generation peptidomimetic hybrid molecule library. The biological properties were investigated in cell-based assays. In a preclinical proof-of-concept study with the radionuclide 68Ga, the impact of the modifications was evaluated by determination of specific tumor uptake, pharmacokinetics and fluorescence-imaging in tumor-bearing mice. Results: The modified hybrid molecules carrying various selected linkers revealed high PSMA-specific binding affinity and effective internalization. The highest tumor-to-background contrast of all modifications investigated was identified for the introduction of a histidine (H) and glutamic acid (E) containing linker ((HE)3-linker) between PSMA-binding motif and chelator. In comparison to the parental core structure, uptake in non-malignant tissue was significantly reduced to a minimum exemplified by an 11-fold reduced spleen uptake from 38.12±14.62 %ID/g to 3.47±1.39 %ID/g (1 h p.i.). The specific tumor uptake of this compound (7.59±0.95 %ID/g, 1 h p.i.) was detected to be significantly higher as compared to the parental tracer PSMA-11. These findings confirmed by PET and fluorescence imaging are accompanied by an enhanced pharmacokinetic profile with accelerated background clearance at early time points post injection. Conclusion: The novel generation of PSMA-targeting hybrid molecules reveal fast elimination, reduced background organ enrichment and high PSMA-specific tumor uptake meeting the key demands for potent tracers in Nuclear Medicine and fluorescence-guided surgery. The approach's efficacy of improving the pharmacokinetic profile highlights the strengths of rational linker design as a powerful tool in strategic hybrid molecule development. |
| 536 | _ | _ | |a 315 - Bildgebung und Radioonkologie (POF4-315) |0 G:(DE-HGF)POF4-315 |c POF4-315 |f POF IV |x 0 |
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| 650 | _ | 7 | |a Optical |2 Other |
| 650 | _ | 7 | |a PSMA |2 Other |
| 650 | _ | 7 | |a Peptides |2 Other |
| 650 | _ | 7 | |a Radiotracer Tissue Kinetics |2 Other |
| 650 | _ | 7 | |a guided-surgery |2 Other |
| 650 | _ | 7 | |a hybrid molecules |2 Other |
| 650 | _ | 7 | |a pharmacokinetic profile |2 Other |
| 650 | _ | 7 | |a prostate cancer |2 Other |
| 700 | 1 | _ | |a Schaefer, Martin |0 P:(DE-HGF)0 |b 1 |
| 700 | 1 | _ | |a Schmidt, Jana |0 P:(DE-He78)748cbc9500371079bf3d34fc41eb828c |b 2 |
| 700 | 1 | _ | |a Bauder-Wuest, Ulrike |b 3 |
| 700 | 1 | _ | |a Roscher, Mareike |0 P:(DE-He78)1a25bc9516a97a13551ebd083356d24f |b 4 |
| 700 | 1 | _ | |a Leotta, Karin |0 P:(DE-He78)c1b2ff9645588258d53aea1ccce6ddcf |b 5 |
| 700 | 1 | _ | |a Haberkorn, Uwe |0 P:(DE-He78)13a0afba029f5f64dc18b25ef7499558 |b 6 |
| 700 | 1 | _ | |a Kopka, Klaus |0 P:(DE-He78)9793347ba83f527b81a22ab75af9378a |b 7 |u dkfz |
| 700 | 1 | _ | |a Eder, Matthias |0 P:(DE-He78)331382460d902d1341dc73db8b990f97 |b 8 |
| 773 | _ | _ | |a 10.2967/jnumed.120.248443 |g p. jnumed.120.248443 - |0 PERI:(DE-600)2040222-3 |n 10 |p 1461-1467 |t Journal of nuclear medicine |v 62 |y 2021 |x 2159-662X |
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