Methodological developments in small animal PET neuroimaging

Positron emission tomography (PET) is a nuclear imaging technique using a multidisciplinary approach to functionally visualize processes in the brain or other living tissue. It is capable to determine the pharmacokinetic and pharmacodynamic properties of a molecule in the CNS, with a low risk of side effects on the subject. This is executed through injection of a radioactively labeled substance into the subject and detection of released gamma photons after radioactive decay of the molecule in the target organ or tissue. Based on these detections, it is possible to reconstruct the distribution of radioligand in the living tissue into an image representing the physiology of the subject.

The present thesis focuses on the methodological development of PET imaging in small animal research and on the support for connecting basic research to human health-related clinical applications in neuroscience. The work underlying this thesis work is divided into three sections. Section 1 consists of the validation of a new PET/MRI small animal imaging system. Since the combination of an MRI magnet with a conventional PET ring could influence the performance of PET measurements, a combined system should be implemented with special care. The results of Study I showed that the combination of PET and MRI components did not affect the performance of the final system and it is capable to effectively conduct consecutive multimodal imaging with functional images from PET and anatomical information of soft tissue. After the validation of the PET system used in this thesis work for imaging, in Section 2 different methodological challenges are presented. Study II focuses on the transporter activity of the blood-brain barrier to highlight the necessity of proper animal model selection while designing pre-clinical PET studies, while in Study III we offer a solution for longitudinal [11C]PBR28 imaging with the validation of SUV as an outcome measure in rodents studies, where blood sampling is a difficult task. Within Section 3 a new animal model and a novel ligand is presented. The previously validated SUV approach from Study III is applied in Study IV during the longitudinal follow-up of the M2CAO stroke rat model to measure changes in the TSPO signal as a mark of neuroinflammation after cortical ischemia. In Study V a knockout animal model was used to validate the novel radioligand [11C]T-773, which was confirmed to bind selectively to the PDE10A enzyme and its distribution and uptake proves its suitability in small animal research.

In conclusion the thesis focuses on the development of novel methodological platforms for small animal imaging PET with the aim to provide advancements in the field of translational neuroscience.

List of scientific papers

I. Nagy K, Tóth M, Major P, Patay G, Egri G, Häggkvist J, Varrone A, Farde L, Halldin C, Gulyás B. Performance evaluation of the small-animal nanoScan PET/MRI system. J Nucl Med. 2013; 54(10): 1825-32.
https://doi.org/10.2967/jnumed.112.119065

II. Tóth M, Häggkvist J, Varrone A, Finnema SJ, Doorduin J, Tokunaga M, Higuchi M, Gulyás B, Halldin C. ABC transporter-dependent brain uptake of the 5-HT1B receptor radioligand [11C]AZ10419369: a comparative PET study in mouse, rat, and guinea pig. EJNMMI Research. 2014; 4:64.
https://doi.org/10.1186/s13550-014-0064-0

III. Tóth M, Doorduin J, Häggkvist J, Varrone A, Amini N, Halldin C, Gulyás B. Positron Emission Tomography studies with [11C]PBR28 in the healthy rodent brain: validating SUV as an outcome measure of neuroinflammation. PLOS ONE. [Accepted]
https://doi.org/10.1371/journal.pone.0125917

IV. Tóth M, Little P, Arnberg F, Häggkvist J, Mulder J, Halldin C, Gulyás B, Holmin S. Acute neuroinflammation in a clinically relevant focal cortical ischemic stroke model in rat: Longitudinal positron emission tomography and immunofluorescent tracking. Brain Struct Funct. 2015.
https://doi.org/10.1007/s00429-014-0970-y

V. Tóth M, Häggkvist J Stepanov V, Takano A, Nakao R, Amini Nahid, Miura S, Kimura H, Taniguchi T, Gulyás B, Halldin C. Molecular Imaging of PDE10A Knockout Mice with a Novel PET Radiotracer: [11C]T-773. Mol Imaging Biol. 2015.
https://doi.org/10.1007/s11307-015-0822-z