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000168092 1001_ $$0P:(DE-He78)584449af653618bdd9539e668604ad74$$aEder, Ann-Christin$$b0
000168092 245__ $$aRational Linker Design to Accelerate Excretion and Reduce Background Uptake of Peptidomimetic PSMA-Targeting Hybrid Molecules.
000168092 260__ $$aNew York, NY$$bSoc.$$c2021
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000168092 500__ $$a2021 Oct;62(10):1461-1467
000168092 520__ $$aThe 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.
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000168092 650_7 $$2Other$$aOptical
000168092 650_7 $$2Other$$aPSMA
000168092 650_7 $$2Other$$aPeptides
000168092 650_7 $$2Other$$aRadiotracer Tissue Kinetics
000168092 650_7 $$2Other$$aguided-surgery
000168092 650_7 $$2Other$$ahybrid molecules
000168092 650_7 $$2Other$$apharmacokinetic profile
000168092 650_7 $$2Other$$aprostate cancer
000168092 7001_ $$0P:(DE-HGF)0$$aSchaefer, Martin$$b1
000168092 7001_ $$0P:(DE-He78)748cbc9500371079bf3d34fc41eb828c$$aSchmidt, Jana$$b2
000168092 7001_ $$aBauder-Wuest, Ulrike$$b3
000168092 7001_ $$0P:(DE-He78)1a25bc9516a97a13551ebd083356d24f$$aRoscher, Mareike$$b4
000168092 7001_ $$0P:(DE-He78)c1b2ff9645588258d53aea1ccce6ddcf$$aLeotta, Karin$$b5
000168092 7001_ $$0P:(DE-He78)13a0afba029f5f64dc18b25ef7499558$$aHaberkorn, Uwe$$b6
000168092 7001_ $$0P:(DE-He78)9793347ba83f527b81a22ab75af9378a$$aKopka, Klaus$$b7$$udkfz
000168092 7001_ $$0P:(DE-He78)331382460d902d1341dc73db8b990f97$$aEder, Matthias$$b8
000168092 773__ $$0PERI:(DE-600)2040222-3$$a10.2967/jnumed.120.248443$$gp. jnumed.120.248443 -$$n10$$p1461-1467$$tJournal of nuclear medicine$$v62$$x2159-662X$$y2021
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