Optimization of the Pharmacokinetic Profile of [<sup>99m</sup>Tc]Tc-N<sub>4</sub>-Bombesin Derivatives by Modification of the Pharmacophoric Gln-Trp Sequence
Current radiolabeled gastrin-releasing peptide receptor (GRPR) ligands usually suffer from high accumulation in GRPR-positive organs (pancreas, stomach), limiting tumor-to-background contrast in the abdomen. In novel N<sub>4</sub>-bombesin derivatives this was addressed by substitutions...
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MDPI AG
2022-09-01
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| Online Access: | https://www.mdpi.com/1424-8247/15/9/1133 |
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| author | Thomas Günther Matthias Konrad León Stopper Jan-Philip Kunert Sebastian Fischer Roswitha Beck Angela Casini Hans-Jürgen Wester |
| author_facet | Thomas Günther Matthias Konrad León Stopper Jan-Philip Kunert Sebastian Fischer Roswitha Beck Angela Casini Hans-Jürgen Wester |
| author_sort | Thomas Günther |
| collection | DOAJ |
| description | Current radiolabeled gastrin-releasing peptide receptor (GRPR) ligands usually suffer from high accumulation in GRPR-positive organs (pancreas, stomach), limiting tumor-to-background contrast in the abdomen. In novel N<sub>4</sub>-bombesin derivatives this was addressed by substitutions at the Gln<sup>7</sup>-Trp<sup>8</sup> site within the MJ9 peptide (<i>H</i>-Pip<sup>5</sup>-phe<sup>6</sup>-Gln<sup>7</sup>-Trp<sup>8</sup>-Ala<sup>9</sup>-Val<sup>10</sup>-Gly<sup>11</sup>-His<sup>12</sup>-Sta<sup>13</sup>-Leu<sup>14</sup>-NH<sub>2</sub>) either by homoserine (Hse<sup>7</sup>), <i>β</i>-(3-benzothienyl) alanine (Bta<sup>8</sup>) or <i>α</i>-methyl tryptophan (<i>α</i>-Me-Trp<sup>8</sup>), with the aim of optimizing pharmacokinetics. We prepared and characterized the peptide conjugates 6-carboxy-1,4,8,11-tetraazaundecane (N<sub>4</sub>)-asp-MJ9, N<sub>4</sub>-asp-[Bta<sup>8</sup>]MJ9, N<sub>4</sub>-[Hse<sup>7</sup>]MJ9 and N<sub>4</sub>-[α-Me-Trp<sup>8</sup>]MJ9, and evaluated these compounds in vitro (GRPR affinity via <i>IC</i><sub>50,inverse</sub>; internalization; lipophilicity via log<i>D</i><sub>7.4</sub>) and in vivo (biodistribution and <i>μ</i>SPECT/CT studies at 1 h post injection (p.i.) in PC-3 tumor-bearing CB17-SCID mice). <sup>99m</sup>Tc-labeling resulted in radiochemical yields (RCYs) > 95%. All <sup>99m</sup>Tc-labeled MJ9 analogues showed comparable or higher GRPR affinity than the external reference [<sup>99m</sup>Tc]Tc-Demobesin 4. Receptor-bound fractions were noticeably higher than that of the reference. Despite a slightly enhanced lipophilicity, all novel MJ9 derivatives revealed improved in vivo pharmacokinetics compared to the reference. The Bta<sup>8</sup>-modified ligand revealed the most favorable tumor-to-abdomen contrast at 1 h p.i. Substitutions at the Gln<sup>7</sup>-Trp<sup>8</sup> site within GRPR ligands hold great potential to modify pharmacokinetics for improved imaging. |
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| last_indexed | 2024-03-09T22:51:31Z |
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| spelling | doaj.art-9bc62e89658747819f19f6c39ceeedf82023-11-23T18:19:15ZengMDPI AGPharmaceuticals1424-82472022-09-01159113310.3390/ph15091133Optimization of the Pharmacokinetic Profile of [<sup>99m</sup>Tc]Tc-N<sub>4</sub>-Bombesin Derivatives by Modification of the Pharmacophoric Gln-Trp SequenceThomas Günther0Matthias Konrad1León Stopper2Jan-Philip Kunert3Sebastian Fischer4Roswitha Beck5Angela Casini6Hans-Jürgen Wester7Department of Chemistry, Technical University of Munich, 85748 Garching, GermanyDepartment of Chemistry, Technical University of Munich, 85748 Garching, GermanyDepartment of Chemistry, Technical University of Munich, 85748 Garching, GermanyDepartment of Chemistry, Technical University of Munich, 85748 Garching, GermanyDepartment of Chemistry, Technical University of Munich, 85748 Garching, GermanyDepartment of Chemistry, Technical University of Munich, 85748 Garching, GermanyDepartment of Chemistry, Technical University of Munich, 85748 Garching, GermanyDepartment of Chemistry, Technical University of Munich, 85748 Garching, GermanyCurrent radiolabeled gastrin-releasing peptide receptor (GRPR) ligands usually suffer from high accumulation in GRPR-positive organs (pancreas, stomach), limiting tumor-to-background contrast in the abdomen. In novel N<sub>4</sub>-bombesin derivatives this was addressed by substitutions at the Gln<sup>7</sup>-Trp<sup>8</sup> site within the MJ9 peptide (<i>H</i>-Pip<sup>5</sup>-phe<sup>6</sup>-Gln<sup>7</sup>-Trp<sup>8</sup>-Ala<sup>9</sup>-Val<sup>10</sup>-Gly<sup>11</sup>-His<sup>12</sup>-Sta<sup>13</sup>-Leu<sup>14</sup>-NH<sub>2</sub>) either by homoserine (Hse<sup>7</sup>), <i>β</i>-(3-benzothienyl) alanine (Bta<sup>8</sup>) or <i>α</i>-methyl tryptophan (<i>α</i>-Me-Trp<sup>8</sup>), with the aim of optimizing pharmacokinetics. We prepared and characterized the peptide conjugates 6-carboxy-1,4,8,11-tetraazaundecane (N<sub>4</sub>)-asp-MJ9, N<sub>4</sub>-asp-[Bta<sup>8</sup>]MJ9, N<sub>4</sub>-[Hse<sup>7</sup>]MJ9 and N<sub>4</sub>-[α-Me-Trp<sup>8</sup>]MJ9, and evaluated these compounds in vitro (GRPR affinity via <i>IC</i><sub>50,inverse</sub>; internalization; lipophilicity via log<i>D</i><sub>7.4</sub>) and in vivo (biodistribution and <i>μ</i>SPECT/CT studies at 1 h post injection (p.i.) in PC-3 tumor-bearing CB17-SCID mice). <sup>99m</sup>Tc-labeling resulted in radiochemical yields (RCYs) > 95%. All <sup>99m</sup>Tc-labeled MJ9 analogues showed comparable or higher GRPR affinity than the external reference [<sup>99m</sup>Tc]Tc-Demobesin 4. Receptor-bound fractions were noticeably higher than that of the reference. Despite a slightly enhanced lipophilicity, all novel MJ9 derivatives revealed improved in vivo pharmacokinetics compared to the reference. The Bta<sup>8</sup>-modified ligand revealed the most favorable tumor-to-abdomen contrast at 1 h p.i. Substitutions at the Gln<sup>7</sup>-Trp<sup>8</sup> site within GRPR ligands hold great potential to modify pharmacokinetics for improved imaging.https://www.mdpi.com/1424-8247/15/9/1133GRPRtechnetium-99mpharmacophore-modified compoundsprostate cancerbreast cancer |
| spellingShingle | Thomas Günther Matthias Konrad León Stopper Jan-Philip Kunert Sebastian Fischer Roswitha Beck Angela Casini Hans-Jürgen Wester Optimization of the Pharmacokinetic Profile of [<sup>99m</sup>Tc]Tc-N<sub>4</sub>-Bombesin Derivatives by Modification of the Pharmacophoric Gln-Trp Sequence Pharmaceuticals GRPR technetium-99m pharmacophore-modified compounds prostate cancer breast cancer |
| title | Optimization of the Pharmacokinetic Profile of [<sup>99m</sup>Tc]Tc-N<sub>4</sub>-Bombesin Derivatives by Modification of the Pharmacophoric Gln-Trp Sequence |
| title_full | Optimization of the Pharmacokinetic Profile of [<sup>99m</sup>Tc]Tc-N<sub>4</sub>-Bombesin Derivatives by Modification of the Pharmacophoric Gln-Trp Sequence |
| title_fullStr | Optimization of the Pharmacokinetic Profile of [<sup>99m</sup>Tc]Tc-N<sub>4</sub>-Bombesin Derivatives by Modification of the Pharmacophoric Gln-Trp Sequence |
| title_full_unstemmed | Optimization of the Pharmacokinetic Profile of [<sup>99m</sup>Tc]Tc-N<sub>4</sub>-Bombesin Derivatives by Modification of the Pharmacophoric Gln-Trp Sequence |
| title_short | Optimization of the Pharmacokinetic Profile of [<sup>99m</sup>Tc]Tc-N<sub>4</sub>-Bombesin Derivatives by Modification of the Pharmacophoric Gln-Trp Sequence |
| title_sort | optimization of the pharmacokinetic profile of sup 99m sup tc tc n sub 4 sub bombesin derivatives by modification of the pharmacophoric gln trp sequence |
| topic | GRPR technetium-99m pharmacophore-modified compounds prostate cancer breast cancer |
| url | https://www.mdpi.com/1424-8247/15/9/1133 |
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