Dataset Information

Divalent 2-(4-Hydroxyphenyl)benzothiazole Bifunctional Chelators for ⁶⁴Cu Positron Emission Tomography Imaging in Alzheimer's Disease.

ABSTRACT: Herein, we report a new series of divalent 2-(4-hydroxyphenyl)benzothiazole bifunctional chelators (BFCs) with high affinity for amyloid β aggregates and favorable lipophilicity for blood-brain barrier penetration. The addition of an alkyl carboxylate ester pendant arm offers high binding affinity toward Cu(II). The novel BFCs form stable ⁶⁴Cu-radiolabeled complexes and exhibit promising partition coefficient (logD) values of 1.05-1.85. Among the five compounds tested, the ⁶⁴Cu-YW-15 complex exhibits significant staining of amyloid β plaques in ex vivo autoradiography studies. In addition, biodistribution studies show that ⁶⁴Cu-YW-15-Me exhibits moderate brain uptake (0.69 ± 0.08 %ID/g) in wild type mice.

SUBMITTER: Terpstra K

PROVIDER: S-EPMC9887732 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Divalent 2-(4-Hydroxyphenyl)benzothiazole Bifunctional Chelators for 64Cu Positron Emission Tomography Imaging in Alzheimer's Disease.

Terpstra Karna K Wang Yujue Y Huynh Truc T TT Bandara Nilantha N Cho Hong-Jun HJ Rogers Buck E BE Mirica Liviu M LM

Inorganic chemistry 20221204 50

Herein, we report a new series of divalent 2-(4-hydroxyphenyl)benzothiazole bifunctional chelators (BFCs) with high affinity for amyloid β aggregates and favorable lipophilicity for blood-brain barrier penetration. The addition of an alkyl carboxylate ester pendant arm offers high binding affinity toward Cu(II). The novel BFCs form stable 64Cu-radiolabeled complexes and exhibit promising partition coefficient (logD) values of 1.05-1.85. Among the five compounds tested, the < ...[more]

PMID: 36463521

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Project description:We have developed a diphosphine (DP) platform for radiolabeling peptides with 99mTc and 64Cu for molecular SPECT and PET imaging, respectively. Two diphosphines, 2,3-bis(diphenylphosphino)maleic anhydride (DPPh) and 2,3-bis(di-p-tolylphosphino)maleic anhydride (DPTol), were each reacted with a Prostate Specific Membrane Antigen-targeted dipeptide (PSMAt) to yield the bioconjugates DPPh-PSMAt and DPTol-PSMAt, as well as an integrin-targeted cyclic peptide, RGD, to yield the bioconjugates DPPh-RGD and DPTol-RGD. Each of these DP-PSMAt conjugates formed geometric cis/trans-[MO2(DPX-PSMAt)2]+ (M = 99mTc, 99gTc, natRe; X = Ph, Tol) complexes when reacted with [MO2]+ motifs. Furthermore, both DPPh-PSMAt and DPTol-PSMAt could be formulated into kits containing reducing agent and buffer components, enabling preparation of the new radiotracers cis/trans-[99mTcO2(DPPh-PSMAt)2]+ and cis/trans-[99mTcO2(DPTol-PSMAt)2]+ from aqueous 99mTcO4- in 81% and 88% radiochemical yield (RCY), respectively, in 5 min at 100 °C. The consistently higher RCYs observed for cis/trans-[99mTcO2(DPTol-PSMAt)2]+ are attributed to the increased reactivity of DPTol-PSMAt over DPPh-PSMAt. Both cis/trans-[99mTcO2(DPPh-PSMAt)2]+ and cis/trans-[99mTcO2(DPTol-PSMAt)2]+ exhibited high metabolic stability, and in vivo SPECT imaging in healthy mice revealed that both new radiotracers cleared rapidly from circulation, via a renal pathway. These new diphosphine bioconjugates also furnished [64Cu(DPX-PSMAt)2]+ (X = Ph, Tol) complexes rapidly, in a high RCY (>95%), under mild conditions. In summary, the new DP platform is versatile: it enables straightforward functionalization of targeting peptides with a diphosphine chelator, and the resulting bioconjugates can be simply radiolabeled with both the SPECT and PET radionuclides, 99mTc and 64Cu, in high RCYs. Furthermore, the DP platform is amenable to derivatization to either increase the chelator reactivity with metallic radioisotopes or, alternatively, modify the radiotracer hydrophilicity. Functionalized diphosphine chelators thus have the potential to provide access to new molecular radiotracers for receptor-targeted imaging.

Project description:High radiolabeling efficiency, preferably to high specific activity, and good stability of the radioimmunoconjugate are essential features for a successful immunoconjugate for imaging or therapy. In this study, the radiolabeling efficiency, in vitro stability, and biodistribution of immunoconjugates with eight different bifunctional chelators labeled with (64)Cu were compared. The anti-CD20 antibody, rituximab, was conjugated to four macrocyclic bifunctional chelators (p-SCN-Bn-DOTA, p-SCN-Bn-Oxo-DO3A, p-SCN-NOTA, and p-SCN-PCTA), three DTPA derivatives (p-SCN-Bn-DTPA, p-SCN-CHX-A″-DTPA, and ITC-2B3M-DTPA), and a macrobicyclic hexamine (sarcophagine) chelator (sar-CO2H) = (1-NH2-8-NHCO(CH2)3CO2H)sar where sar = sarcophagine = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane). Radiolabeling efficiency under various conditions, in vitro stability in serum at 37 °C, and in vivo biodistribution and imaging in normal mice over 48 h were studied. All chelators except sar-CO2H were conjugated to rituximab by thiourea bond formation with an average of 4.9 ± 0.9 chelators per antibody molecule. Sar-CO2H was conjugated to rituximab by amide bond formation with 0.5 chelators per antibody molecule. Efficiencies of (64)Cu radiolabeling were dependent on the concentration of immunoconjugate. Notably, the (64)Cu-NOTA-rituximab conjugate demonstrated the highest radiochemical yield (95%) under very dilute conditions (31 nM NOTA-rituximab conjugate). Similarly, sar-CO-rituximab, containing 1/10th the number of chelators per antibody compared to that of other conjugates, retained high labeling efficiency (98%) at an antibody concentration of 250 nM. In contrast to the radioimmunoconjugates containing DTPA derivatives, which demonstrated poor serum stability, all macrocyclic radioimmunoconjugates were very stable in serum with <6% dissociation of (64)Cu over 48 h. In vivo biodistribution profiles in normal female Balb/C mice were similar for all the macrocyclic radioimmunoconjugates with most of the activity remaining in the blood pool up to 48 h. While all the macrocyclic bifunctional chelators are suitable for molecular imaging using (64)Cu-labeled antibody conjugates, NOTA and sar-CO2H show significant advantages over the others in that they can be radiolabeled rapidly at room temperature, under dilute conditions, resulting in high specific activity.

Dataset Information

Divalent 2-(4-Hydroxyphenyl)benzothiazole Bifunctional Chelators for ⁶⁴Cu Positron Emission Tomography Imaging in Alzheimer's Disease.

Publications

Divalent 2-(4-Hydroxyphenyl)benzothiazole Bifunctional Chelators for <sup>64</sup>Cu Positron Emission Tomography Imaging in Alzheimer's Disease.

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