TY - JOUR
T1 - Toward Bifunctional Chelators for Thallium-201 for Use in Nuclear Medicine
AU - Rigby, Alex
AU - Firth, George
AU - Rivas, Charlotte
AU - Pham, Truc
AU - Kim, Jana
AU - Phanopoulos, Andreas
AU - Wharton, Luke
AU - Ingham, Aidan
AU - Li, Lily
AU - Ma, Michelle T.
AU - Orvig, Chris
AU - Blower, Philip J.
AU - Terry, Samantha Y.A.
AU - Abbate, Vincenzo
N1 - Funding Information:
A.R. would like to acknowledge funding from the EPSRC Centre for Doctoral Training in Medical Imaging (EP/L015226/1). This work was also supported by the Rosetrees Trust (M786), Wellcome/EPSRC Centre for Medical Engineering at King’s College London (WT 203148/Z/16/Z), EPSRC Programme Grant (EP/S032789/1, “MITHRAS″), and a Cancer Research UK Career Establishment Award (C63178/A24959). This research was also funded in part by the Wellcome Trust (WT 203148/Z/16/Z). We gratefully acknowledge the Natural Sciences and Engineering Research Council (NSERC) of Canada for a Discovery Grant (RGPIN-42394-13) and for NSERC CREATE IsoSiM at TRIUMF studentships (A.I., L.L., L.W.); TRIUMF receives federal funding via a contribution agreement with the National Research Council of Canada. For the purpose of open access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/7/20
Y1 - 2022/7/20
N2 - Auger electron therapy exploits the cytotoxicity of low-energy electrons emitted during radioactive decay that travel very short distances (typically <1 μm).
201Tl, with a half-life of 73 h, emits ∼37 Auger and other secondary electrons per decay and can be tracked in vivo as its gamma emissions enable SPECT imaging. Despite the useful nuclear properties of
201Tl, satisfactory bifunctional chelators to incorporate it into bioconjugates for molecular targeting have not been developed. H
4pypa, H
5decapa, H
4neunpa-NH
2, and H
4noneunpa are multidentate N- A nd O-donor chelators that have previously been shown to have high affinity for
111In,
177Lu, and
89Zr. Herein, we report the synthesis and serum stability of [
nat/201Tl]Tl
3+complexes with H
4pypa, H
5decapa, H
4neunpa-NH
2, and H
4noneunpa. All ligands quickly and efficiently formed complexes with [
201Tl]Tl
3+that gave simple single-peak radiochromatograms and showed greatly improved serum stability compared to DOTA and DTPA. [
natTl]Tl-pypa was further characterized using nuclear magnetic resonance spectroscopy (NMR), mass spectroscopy (MS), and X-ray crystallography, showing evidence of the proton-dependent presence of a nine-coordinate complex and an eight-coordinate complex with a pendant carboxylic acid group. A prostate-specific membrane antigen (PSMA)-targeting bioconjugate of H
4pypa was synthesized and radiolabeled. The uptake of [
201Tl]Tl-pypa-PSMA in DU145 PSMA-positive and PSMA-negative prostate cancer cells was evaluated in vitro and showed evidence of bioreductive release of
201Tl and cellular uptake characteristic of unchelated [
201Tl]TlCl. SPECT/CT imaging was used to probe the in vivo biodistribution and stability of [
201Tl]Tl-pypa-PSMA. In healthy animals, [
201Tl]Tl-pypa-PSMA did not show the myocardial uptake that is characteristic of unchelated
201Tl. In mice bearing DU145 PSMA-positive and PSMA-negative prostate cancer xenografts, the uptake of [
201Tl]Tl-pypa-PSMA in DU145 PSMA-positive tumors was higher than that in DU145 PSMA-negative tumors but insufficient for useful tumor targeting. We conclude that H
4pypa and related ligands represent an advance compared to conventional radiometal chelators such as DOTA and DTPA for Tl
3+chelation but do not resist dissociation for long periods in the biological environment due to vulnerability to reduction of Tl
3+and subsequent release of Tl
+. However, this is the first report describing the incorporation of [
201Tl]Tl
3+into a chelator-peptide bioconjugate and represents a significant advance in the field of
201Tl-based radiopharmaceuticals. The design of the next generation of chelators must include features to mitigate this susceptibility to bioreduction, which does not arise for other trivalent heavy radiometals.
AB - Auger electron therapy exploits the cytotoxicity of low-energy electrons emitted during radioactive decay that travel very short distances (typically <1 μm).
201Tl, with a half-life of 73 h, emits ∼37 Auger and other secondary electrons per decay and can be tracked in vivo as its gamma emissions enable SPECT imaging. Despite the useful nuclear properties of
201Tl, satisfactory bifunctional chelators to incorporate it into bioconjugates for molecular targeting have not been developed. H
4pypa, H
5decapa, H
4neunpa-NH
2, and H
4noneunpa are multidentate N- A nd O-donor chelators that have previously been shown to have high affinity for
111In,
177Lu, and
89Zr. Herein, we report the synthesis and serum stability of [
nat/201Tl]Tl
3+complexes with H
4pypa, H
5decapa, H
4neunpa-NH
2, and H
4noneunpa. All ligands quickly and efficiently formed complexes with [
201Tl]Tl
3+that gave simple single-peak radiochromatograms and showed greatly improved serum stability compared to DOTA and DTPA. [
natTl]Tl-pypa was further characterized using nuclear magnetic resonance spectroscopy (NMR), mass spectroscopy (MS), and X-ray crystallography, showing evidence of the proton-dependent presence of a nine-coordinate complex and an eight-coordinate complex with a pendant carboxylic acid group. A prostate-specific membrane antigen (PSMA)-targeting bioconjugate of H
4pypa was synthesized and radiolabeled. The uptake of [
201Tl]Tl-pypa-PSMA in DU145 PSMA-positive and PSMA-negative prostate cancer cells was evaluated in vitro and showed evidence of bioreductive release of
201Tl and cellular uptake characteristic of unchelated [
201Tl]TlCl. SPECT/CT imaging was used to probe the in vivo biodistribution and stability of [
201Tl]Tl-pypa-PSMA. In healthy animals, [
201Tl]Tl-pypa-PSMA did not show the myocardial uptake that is characteristic of unchelated
201Tl. In mice bearing DU145 PSMA-positive and PSMA-negative prostate cancer xenografts, the uptake of [
201Tl]Tl-pypa-PSMA in DU145 PSMA-positive tumors was higher than that in DU145 PSMA-negative tumors but insufficient for useful tumor targeting. We conclude that H
4pypa and related ligands represent an advance compared to conventional radiometal chelators such as DOTA and DTPA for Tl
3+chelation but do not resist dissociation for long periods in the biological environment due to vulnerability to reduction of Tl
3+and subsequent release of Tl
+. However, this is the first report describing the incorporation of [
201Tl]Tl
3+into a chelator-peptide bioconjugate and represents a significant advance in the field of
201Tl-based radiopharmaceuticals. The design of the next generation of chelators must include features to mitigate this susceptibility to bioreduction, which does not arise for other trivalent heavy radiometals.
UR - http://www.scopus.com/inward/record.url?scp=85134721502&partnerID=8YFLogxK
U2 - 10.1021/acs.bioconjchem.2c00284
DO - 10.1021/acs.bioconjchem.2c00284
M3 - Article
C2 - 35801668
AN - SCOPUS:85134721502
SN - 1520-4812
VL - 33
SP - 1422
EP - 1436
JO - Bioconjugate chemistry
JF - Bioconjugate chemistry
IS - 7
ER -