Abstract
Abnormalities in zinc homeostasis are indicated in many human diseases, including Alzheimer disease (AD). 63Zn-zinc citrate was developed as a positron emission tomography (PET) imaging probe of zinc transport and used in a first-in-human study in 6 healthy elderly individuals and 6 patients with clinically confirmed AD. Dynamic PET imaging of the brain was performed for 30 minutes following intravenous administration of 63Zn-zinc citrate (∼330 MBq). Subsequently, body PET images were acquired. Urine and venous blood were analyzed to give information on urinary excretion and pharmacokinetics. Regional cerebral 63Zn clearances were compared with 11C-Pittsburgh Compound B (11C-PiB) and 18F-fluorodeoxyglucose (18F-FDG) imaging data. 63Zn-zinc citrate was well tolerated in human participants with no adverse events monitored. Tissues of highest uptake were liver, pancreas, and kidney, with moderate uptake being seen in intestines, prostate (in males), thyroid, spleen, stomach, pituitary, and salivary glands. Moderate brain uptake was observed, and regional dependencies were observed in 63Zn clearance kinetics in relationship with regions of high amyloid-β plaque burden (11C-PiB) and 18F-FDG hypometabolism. In conclusion, zinc transport was successfully imaged in human participants using the PET probe 63Zn-zinc citrate. Primary sites of uptake in the digestive system accent the role of zinc in gastrointestinal function. Preliminary information on zinc kinetics in patients with AD evidenced regional differences in clearance rates in correspondence with regional amyloid-β pathology, warranting further imaging studies of zinc homeostasis in patients with AD.
Highlights
Abnormalities in zinc homeostasis are indicated in many human diseases, including Alzheimer disease (AD). 63Zn-zinc citrate was developed as a positron emission tomography (PET) imaging probe of zinc transport and used in a first-in-human study in 6 healthy elderly individuals and 6 patients with clinically confirmed AD
What are the major tissues that take up zinc and what potential clinical role might 63Zn-PET play in these tissues? Second, can 63Zn-PET be useful to evaluate the uptake and turnover of zinc in brains of patients with AD? The answer to the first question was predominantly liver, with moderately high uptake of zinc in the pancreas, kidney, and GI tract
A first-in-human PET imaging study of 63Zn-zinc citrate was performed in patients with AD and healthy elderly participants
Summary
Abnormalities in zinc homeostasis are indicated in many human diseases, including Alzheimer disease (AD). 63Zn-zinc citrate was developed as a positron emission tomography (PET) imaging probe of zinc transport and used in a first-in-human study in 6 healthy elderly individuals and 6 patients with clinically confirmed AD. The potential role of positron emission tomography (PET) imaging in assessing metal homeostasis in brains of patients with AD has recently motivated the development of 18F-CABS13 as a zinc ionophore molecule that is able to permeate the blood–brain barrier (BBB) and shows differences in brain uptake in APP/PS1 mice relative to age-matched wild-type mice.[10] Clearly, information on the dynamics of the metal ions themselves in preclinical models of AD and in patients with AD would provide important information that could support (or call into question) the so-called ‘‘metals hypothesis’’ of AD.[11] According to this hypothesis, zinc and copper may play a key role in the formation and stabilization of neurotoxic oligomers of amyloid b-proteins.[11] To address this need, we have recently developed 63Zn-zinc citrate as a PET probe of zinc transport.[12] The 38.5-minute radioisotopic halflife of 63Zn allows imaging studies of duration up to 2 to 3 hours to evaluate biodistribution and moderately rapid turnover processes in tissues. Biodistribution of 63Zn-zinc citrate in mice was found to be predominantly within the gastrointestinal (GI) tract, with low but significant uptake in brain regions.[12]
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