# Physiologically relevant forms of Tc- and Re-pyrophosphate radioactive tracers and the basis of their transthyretin amyloid sensitivity

## TL;DR

This study identifies the structure of Tc-PYP, a radioactive tracer used in diagnosing amyloid diseases, and explains its sensitivity to certain amyloids.

## Contribution

The paper determines the physiological structure of Tc-PYP and Re-PYP tracers and links their structure to amyloid sensitivity.

## Key findings

- Tc-PYP and Re-PYP tracers form octahedral Re(IV)/Tc(IV) diaqua dipyrophosphate complexes under physiological conditions.
- The flexible geometry of these complexes explains their high affinity for certain amyloids.
- The study provides a theoretical and experimental basis for the diagnostic behavior of these tracers.

## Abstract

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\begin{document}$${^{99\text {m}}}$$\end{document}Technetium Pyrophosphate (\documentclass[12pt]{minimal}
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\begin{document}$${^{99\text {m}}}$$\end{document}Tc-PYP(Sn)) is a commonly used radioactive tracer, with a long history of use in diagnosing bone-related diseases and a newfound purpose in differentiating ATTR and AL amyloidoses. Despite its ubiquity, basic aspects like its composition and structure are as of yet undetermined, and its method of binding to ATTR amyloid fibrils is likewise hitherto unknown. This complicates the diagnostic process, as it introduces inexplicable losses of sensitivity in some ATTR and AL variants. In this paper we report the results of our comprehensive investigation into the physiologically active structure of Tc-PYP and its closely related, but experimentally more approachable counterpart, Re-PYP, built on a robust theoretical basis and backed up by multiple spectroscopic methods (focusing on the rhenium analogue). We conclude that the Re/Tc-PYP tracers possess a flexible geometry, but ultimately appear as octahedral Re(IV)/Tc(IV) diaqua dipyrophosphate complexes under physiological conditions, and predict that this structure is the reason for the high affinity of \documentclass[12pt]{minimal}
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\begin{document}$$\phantom{0}^{99m}$$\end{document}Tc-PYP for certain amyloids.