Non-invasive radionuclide imaging of trace metal trafficking in health and disease: "PET metallomics"

Abstract

Several specific metallic elements must be present in the human body to maintain health and function. Maintaining the correct quantity (from trace to bulk) and location at the cell and tissue level is essential. The study of the biological role of metals has become known as metallomics. While quantities of metals in cells and tissues can be readily measured in biopsy and autopsy samples by destructive analytical techniques, their trafficking and its role in health and disease are poorly understood. Molecular imaging with radionuclides - positron emission tomography (PET) and single photon emission computed tomography (SPECT) - is emerging as a means to non-invasively study the acute trafficking of essential metals between organs, non-invasively and in real time, in health and disease. PET scanners are increasingly widely available in hospitals, and methods for producing radionuclides of some of the key essential metals are developing fast. This review summarises recent developments in radionuclide imaging technology that permit such investigations, describes the radiological and physicochemical properties of key radioisotopes of essential trace metals and useful analogues, and introduces current and potential future applications in preclinical and clinical investigations to study the biology of essential trace metals in health and disease.

Fig. 1. Radioactive metals allow for the non-invasive study of essential trace metals in vivo in health and disease. (A) A summary of diseases implicated in metal homeostasis dysregulation that can be studied using radionuclide imaging. (B) Example of a total-body [¹⁸F]FDG PET scan highlighting glucose avid tissues. (C) Periodic table colour-coded to highlight elements with useful radioisotopes that can be used to image trace metal biology. Radionuclides with metallomics applications are discussed in individual sections throughout this review.

Fig. 2. Applications of potassium mimetics in nuclear medicine. (A) Representative myocardial perfusion imaging with ^99mTc-Sestamibi SPECT and ⁸²Rb-PET. From top to bottom: axial apical, mid and basal sections, coronal and sagittal slices. (B) Clinical CT scan of a lung cancer patient (top) with a corresponding axial section from a ⁸²Rb PET scan (bottom) (courtesy of A. Groves, UCL). Myocardial perfusion images are adapted and reproduced with permission under a Creative Commons Attribution (CC-BY) License from ref. , Front. Med., copyright© 2015.

Fig. 3. Biodistribution and pharmacokinetics of ⁵²Mn, administered i.v. as MnCl₂, in healthy mice. (A) Representative serial maximum intensity projection (MIP) PET images of healthy mice at 1 and 72 hours p.i. ⁵²Mn is primarily distributed to abdominal organs such as liver (L), kidney (K) and intestines. At 72 h p.i., ⁵²Mn is found predominantly in the kidneys, pancreas (P) and salivary glands (SG). (B) Ex vivo biodistribution of ⁵²Mn in aqueous solution following i.v. injection at 1 and 24 h p.i. Adapted with permission under a Creative Commons Attribution (CC-BY) License from ref. , PLoS One, copyright© 2017.

Fig. 4. Assessment of β-cell mass and function by PET/MRI. (A) PET/MRI images of the pancreas in mice following co-injection of the β-cell specific radiotracer [⁶⁴Cu]Cu-NODAGA-⁴⁰Lys-Exendin-4 and paramagnetic MnCl₂. (B) LA-ICP-MS images revealed typical metal tissue distribution for the pancreas, notably high Zn concentrated in the islets (highlighted by arrows) co-localised with [⁶⁴Cu]Ex4 autoradiographs. Interestingly, Mn was found predominately in the exocrine tissue at 1 h p.i., and transitioned to islets by 24 h p.i. Adapted with permission under a Creative Commons Attribution (CC-BY) License from ref. , Theranostics, copyright© 2020.

Fig. 5. Imaging cobalt trafficking with ⁵⁵Co-PET in a subcutaneous colon cancer mouse model. Biodistribution of ⁵⁵Co in female Nu/Nu mice bearing subcutaneous HCT-116 colon tumours on the upper right flank. (A) PET images at 24 h and 48 h post i.v. administration of ⁵⁵CoCl₂ demonstrate uptake in the tumour (T) and clearance through the liver (L), kidney (K), and intestines. (B) Ex vivo biodistribution at 2, 24 and 48 h p.i. Adapted with permission under a Creative Commons Attribution (CC-BY) License from ref. , Mol. Imaging, copyright© 2015.

Fig. 6. Comparison of i.v. and orally administered acetate-buffered [⁶⁴Cu]CuCl₂ in healthy human subjects. Whole-body MIPs in two healthy individuals, showing redistribution of ⁶⁴Cu from the bloodstream to the peripheral organs with pronounced hepatic accumulation following i.v. injection of acetate-buffered ⁶⁴Cu (upper panels), while the oral administration of ⁶⁴Cu resulted in significant ⁶⁴Cu signal in the intestines and slower distribution of ⁶⁴Cu throughout the body due to limited absorption from the gastrointestinal tract. Adapted with permission under a Creative Commons Attribution (CC-BY) License from ref. , EJNMMI Radiopharmacy and Chemistry, copyright© 2020.

Fig. 7. Clinical PET imaging with i.v. injected [⁶⁴Cu]Cu–chloride to detect biochemical relapse in prostate cancer patients. The tumour is located in the pelvic region and is indicated with an arrow. This research was originally published in J. Nucl. Med., Piccardo et al.⁶⁴CuCl₂ PET/CT in Prostate Cancer Relapse. J. Nucl. Med., 2018, 59, 444–451. © SNMMI.

Fig. 8. Preclinical ⁶⁴Cu-PET imaging in a mouse model of WD. (A) Representative PET/CT images 24 hours after oral administration of [⁶⁴Cu]Cu–chloride visualise hepatic copper overload and urinary excretion during disease progression in the Atp7B^−/− mouse model of WD, compared to reduced uptake in the wildtype control (B). Red arrows and white arrows identify ⁶⁴Cu present in the liver and gastrointestinal tract respectively. Adapted with permission under a Creative Commons Attribution (CC-BY) License from ref. , PLoS One, copyright© 2012.

Fig. 9. Imaging treatment response in a mouse model of Menkes disease with ⁶⁴Cu-PET. Preclinical PET imaging with i.v. injected [⁶⁴Cu]Cu–chloride to assess ⁶⁴Cu redistribution after treatment with disulfiram and d-penicillamine. This research was originally published in J. Nucl. Med. Nomura et al. PET imaging analysis with ⁶⁴Cu in disulfiram treatment for aberrant copper biodistribution in Menkes disease mouse model. J. Nucl. Med., 2014, 55, 845–851. © SNMMI.

Fig. 10. Imaging copper trafficking in Alzheimer's disease with ⁶⁴Cu-PET. Preclinical PET imaging of the head after i.v. injection of [⁶⁴Cu]Cu–GTSM demonstrating alterations in the brain and spinal cord copper clearance in a mouse model of AD (TASTPM). This research was originally published in J. Nucl. Med. Torres et al. PET Imaging of Copper Trafficking in a Mouse Model of Alzheimer's Disease. J. Nucl. Med., 2016, 57, 109–114. © SNMMI.

Fig. 11. ⁶³Zn-PET can be used to study zinc trafficking in vivo up to 2 hours. (A) Serial small-animal PET images of healthy male B6.SJL mice after i.v. administration of [⁶³Zn]Zn–citrate demonstrate predominant abdominal uptake. (B) CT, PET and fused PET/CT images are shown in a representative patient with Alzheimer's disease and healthy elderly participant (C) at 45 to 70 minutes p.i. of [⁶³Zn]Zn–citrate. Uptake was observed in the liver, pancreas, spleen, kidneys, intestines and bone marrow with no qualitative differences between the groups. Adapted with permission from Degrado et al.

Fig. 12. ⁶²Zn-PET can be used to study zinc trafficking in vivo over 2 days despite complex decay via⁶²Cu. (A) Frontal maximum intensity projection (MIP) PET/CT images of female BALB/c mice (10–11 weeks old) injected i.v. with [⁶²Zn]Zn–citrate (left) and [⁶⁴Cu]Cu–citrate (right). (B) Ex vivo biodistribution at 24 h p.i. shows significant pancreatic uptake for ⁶²Zn contrasting the lower uptake observed with ⁶⁴Cu. Adapted with permission from ref. .

George Firth

Julia E. Blower

Joanna J. Bartnicka

Aishwarya Mishra

Aidan M. Michaels

Philip J. Blower