PT  - JOURNAL ARTICLE
AU  - GU, JIWEI
AU  - Zheng, MingQiang
AU  - Qiu, Lin
AU  - Felchner, Zachary
AU  - Zhang, Li
AU  - Ropchan, Jim
AU  - J. Gropler, Robert
AU  - Carson, Richard
AU  - Tu, Zhude
AU  - Huang, Yiyun
AU  - Hillmer, Ansel
TI  - <strong>Evaluation of [18F]TZ4877, a radioligand targeting the Sphingosine 1 Phosphate Receptor 1, for imaging neuroimmune response in Nonhuman Primates</strong>
DP  - 2023 Jun 01
TA  - Journal of Nuclear Medicine
PG  - P424--P424
VI  - 64
IP  - supplement 1
4099  - http://jnm.snmjournals.org/content/64/supplement_1/P424.short
4100  - http://jnm.snmjournals.org/content/64/supplement_1/P424.full
SO  - J Nucl Med2023 Jun 01; 64
AB  - P424 Introduction: The sphingosine-1-phosphate receptor-1 (S1PR1) is involved in regulating microglia and astrocyte responses to neuroimmune stimuli, and generally considered to be neuroprotective or anti-inflammatory. The S1PR1-specific radioligand [11C]CS1P1 is a promising candidate for human imaging, supported by whole body dosimetry studies1 and pilot studies in MS patients2, but it exhibits protracted kinetic properties. Therefore, a need remains for a S1PR­­­1 radioligand with faster kinetic properties. The goal of this work was to evaluate a 18F-labeled radiotracer, [18F]TZ4877, including comparison with [11C]CS1P1, in nonhuman primates.Methods: [18F]TZ4877 was prepared via nucleophilic substitution of a tosylate precursor with K[18F]/F- followed by deprotection, while [11C]CS1P1 was prepared by methylation of t-Bu-protected precursor followed by deprotection. PET data were acquired with a Focus-220 scanner in three rhesus monkeys (3 M; 6.5-12.5 years). Bolus injection of radiotracer was followed by up to 240 min ([18F]TZ4877) or 120 min ([11C]CS1P1) of PET acquisition, with arterial plasma assay and metabolite analysis to measure the parent input function and plasma free fraction (fP). Baseline [18F]TZ4877 and [11C]CS1P1 scans were acquired in two animals each. Challenge [18F]TZ4877 scans were acquired 167-196 min after 1 ng/kg endotoxin administration (n=2). Blocking studies were acquired 33 min after administration of 0.4-0.8 mg/kg TZ82112, which is highly specific for S1PR1. Data were analyzed with one- and two- tissue compartment models (1TCM & 2TCM) and multilinear analysis (MA1) to estimate volumes of distribution (VT).Results: [18F]TZ4877 and [11C]CS1P1 were prepared in high molar activity (45-418 MBq/nmol at time of injection) and >96% radiochemical purity. At baseline, [18F]TZ4877 compared with [11C]CS1P1 exhibited lower parent fractions (22-30% vs 55-80% at 60 min) and comparable fP values (0.6-0.9% vs 0.5-0.9%). Tissue kinetics were faster for [18F]TZ4877, and data were best modeled by 2TCM with regional VT values ranging from 2.2-5.1 mL/cm3. [11C]CS1P1 SUVs continued to increase at 120 min post-injection. 2TCM VT estimates were unstable (s.e.>45%) while 1TCM yielded poor fits. MA1 (t*=20 min) yielded [11C]CS1P1 VT estimates ranging from 5.2-18.2 mL/cm3. Endotoxin increased [18F]TZ4877 VT in all brain regions for both animals, with a robust mean VT increase of 36% (range 9-59%) in one animal and modest mean increase of 6% (range 1-13%) in the other. Blocking with TZ82112 increased [18F]TZ4877 fP to 1.6-2.0%, resulting in dose-dependent reductions in [18F]TZ4877 VT/fP throughout the brain. Conclusions: [18F]TZ4877 exhibits suitable properties for imaging S1PR1 in nonhuman primates, with faster kinetic properties than [11C]CS1P1.Funding: This work was supported by P30DA046345, P41EB025815, NS103988, and NS075527References: 1) Brier MR, et al. Phase 1 evaluation of 11C-CS1P1 to assess safety and dosimetry in human participants. J Nucl Med. 2022.2) Brier MR, et al. Measuring sphingosine-1-phosphate receptor-1 in multiple sclerosis using a novel positron emission tomography radioligand. ACTRIMS Forum 2022-Poster Presentations. 2022