Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: ¹⁸F-BCPP-EF, ¹¹C-SA-4503, and ¹¹C-UCB-J

Abstract

Mitochondrial complex 1 is involved in maintaining brain bioenergetics; σ-1 receptor responds to neuronal stress; and synaptic vesicle protein 2A reflects synaptic integrity. Expression of each of these proteins is altered in neurodegenerative diseases. Here, we characterize the kinetic behavior of 3 PET radioligands-18 F-BCPP-EF, 11 C-SA-4503, and 11 C-UCB-J-for the measurement of mitochondrial complex 1, σ-1 receptor, and synaptic vesicle protein 2A, respectively, and determine appropriate analysis workflows for their application in future studies of the in vivo molecular pathology of these diseases. Methods: Twelve human subjects underwent dynamic PET scans with each radioligand, including associated arterial blood sampling. A range of kinetic models was investigated to identify an optimal kinetic analysis method for each radioligand and a suitable acquisition duration. Results: All 3 radioligands readily entered the brain and yielded heterogeneous uptake consistent with the known distribution of the targets. The optimal models determined for the regional estimates of volume of distribution were multilinear analysis 1 (MA1) and the 2-tissue-compartment model for 18 F-BCPP-EF, MA1 for 11 C-SA-4503, and both MA1 and the 1-tissue-compartment model for 11 C-UCB-J. Acquisition times of 70, 80, and 60 min for 18 F-BCPP-EF, 11 C-SA-4503, 11 C-UCB-J, respectively, provided good estimates of regional volume of distribution values. An effect of age was observed on 18 F-BCPP-EF and 11 C-UCB-J signal in the caudate. Conclusion: These ligands can be assessed for their potential to stratify patients or monitor the progression of molecular neuropathology in neurodegenerative diseases.

Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats

“…To investigate if non-specific uptake was influencing our findings, we repeated the analysis using DVR as the outcome, which uses the centrum semiovale as a pseudoreference region to adjust for non-specific uptake in brain. The centrum semiovale is a white matter region that is largely devoid of SV2A and displays very low uptake of [ 11 C] UCB-J 31,44,48 . Nevertheless, there is a small amount of displacement of [ 11 C]UCB-J uptake in the centrum semiovale by a drug, levetiracetam, that is selective for SV2A 31 , suggesting that there is a degree of specific binding in the centrum semiovale.…”

“…Regional TAC and arterial input function data were analysed together using the one-tissue compartment model (1TCM), which has been shown to produce reliable estimates of [ 11 C]UCB-J volumes of distribution (V T ) 44,48 .…”

“…For each subject, regional corrected GMV is expressed as proportions of the subject's own total brain volume, including grey matter, white matter and cerebrospinal fluid, to account for intersubject variation in total brain volume. Furthermore, regional DVR was obtained by use of the centrum semiovale as a pseudoreference region 31,48 .…”

Positron emission tomography imaging of renal mitochondria is a powerful tool in the study of acute and progressive kidney disease models

“…In addition, 18 F-BCPP-EF, a close analog of 18 F-BCPP-BF with almost identical pharmacologic activity, has already been approved following assessments and has begun to be used in several clinical brain studies, including trials concerning normal aging and Alzheimer's and Parkinson's diseases in the United States, European Union, and Japan. 42 Overall, the present study proposed a new PET imaging modality using 18 F-BCPP-BF to assess the mitochondrial status in live intact kidneys. Its highly quantitative and less invasive aspects should open various applications and contribute to the better understanding of the roles of mitochondria in the onset and progression of kidney diseases, possibly leading to establishment of novel diagnostic or pharmaceutical approaches.…”

Visualizing mitochondrial (dys)function using positron emission tomography imaging

“…18 F-BCPP-BF requires further study, but 18 F-BCPP-EF is a close analogue of 18 F-BCPP-BF with a similar pharmacological profile that shows promise in human brain imaging studies to investigate normal aging and dementia. 9 Future studies could test PET imaging with 18 F-BCPP-EF as a novel method to investigate mitochondrial dysfunction in human kidneys.…”