Synthesis and: Ex vivo biological evaluation of gallium-68 labelled NODAGA chelates assessing cardiac uptake and retention

TY - JOUR

T1 - Synthesis and

T2 - Ex vivo biological evaluation of gallium-68 labelled NODAGA chelates assessing cardiac uptake and retention

AU - Osborne, Bradley E.

AU - Yue, Thomas T.C.

AU - Waters, Edward C.T.

AU - Baark, Friedrich

AU - Southworth, Richard

AU - Long, Nicholas J.

N1 - Funding Information: We would like to thank the King’s College London & Imperial College London EPSRC Centre for Doctoral Training in Medical Imaging (EP/L015226/1) and the EPSRC Programme grants for Next Generation Molecular Imaging and Therapy with Radionuclides (EP/S032789/1 “MITHRAS”, EP/ S019901/1 “RedOx_KCL”) funding, and Imperial College London for studentship funding for B. E. O. Publisher Copyright: © The Royal Society of Chemistry.

PY - 2021/11/7

Y1 - 2021/11/7

N2 - Radiolabelled lipophilic cations can be used to non-invasively report on mitochondrial dysfunction in diseases such as cardiovascular disease, cardiotoxicity and cancer. Several such lipophilic cations are currently used clinically to map myocardial perfusion using SPECT imaging. Since PET offers significant advantages over SPECT in terms of sensitivity, resolution and the capacity for dynamic imaging to allow pharmacokinetic modelling, we have synthesised and radiolabelled a series of NODAGA-based radiotracers, with triarylphosphonium-functionalisation, with gallium-68 to develop PET-compatible cationic complexes. To evaluate their capacity to report upon mitochondrial membrane potential, we assessed their pharmacokinetic profiles in isolated perfused rat hearts before and after mitochondrial depolarisation with the ionophore CCCP. All three tracers radiolabel with over 96% RCY, with log D7.4 values above -0.4 observed for the most lipophilic example of this family of radiotracers. The candidate tracer [68Ga]Ga4c exhibited non-preferential uptake in healthy cardiac tissue over CCCP-infused cardiac tissue. While this approach does show promise, the lipophilicity of this family of probes needs improving in order for them to be effective cardiac imaging agents. This journal is

AB - Radiolabelled lipophilic cations can be used to non-invasively report on mitochondrial dysfunction in diseases such as cardiovascular disease, cardiotoxicity and cancer. Several such lipophilic cations are currently used clinically to map myocardial perfusion using SPECT imaging. Since PET offers significant advantages over SPECT in terms of sensitivity, resolution and the capacity for dynamic imaging to allow pharmacokinetic modelling, we have synthesised and radiolabelled a series of NODAGA-based radiotracers, with triarylphosphonium-functionalisation, with gallium-68 to develop PET-compatible cationic complexes. To evaluate their capacity to report upon mitochondrial membrane potential, we assessed their pharmacokinetic profiles in isolated perfused rat hearts before and after mitochondrial depolarisation with the ionophore CCCP. All three tracers radiolabel with over 96% RCY, with log D7.4 values above -0.4 observed for the most lipophilic example of this family of radiotracers. The candidate tracer [68Ga]Ga4c exhibited non-preferential uptake in healthy cardiac tissue over CCCP-infused cardiac tissue. While this approach does show promise, the lipophilicity of this family of probes needs improving in order for them to be effective cardiac imaging agents. This journal is

UR - https://www.scopus.com/pages/publications/85118219871

U2 - 10.1039/d1dt02224e

DO - 10.1039/d1dt02224e

M3 - Article

AN - SCOPUS:85118219871

SN - 1477-9226

VL - 50

SP - 14695

EP - 14705

JO - Dalton Transactions

JF - Dalton Transactions

IS - 41

ER -