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First in-human PET study and kinetic evaluation of [¹⁸F]AS2471907 for imaging 11β-hydroxysteroid dehydrogenase type 1.

ABSTRACT: 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes enzymatic conversion of cortisone into the stress hormone cortisol. This first-in-human brain imaging study characterizes the kinetic modeling and test-retest reproducibility of [¹⁸F]AS2471907, a novel PET radiotracer for 11β-HSD1. Eight individuals underwent one 180-min (n = 4) or two 240-min (n = 4) [¹⁸F]AS2471907 PET brain scans (12 total) acquired on the high-resolution research tomograph (HRRT) scanner with arterial blood sampling. Imaging data were modeled with 1-tissue (1T) and 2-tissue (2T) compartment models and with multilinear analysis (MA1) to estimate [¹⁸F]AS2471907 availability (V_T). [¹⁸F]AS2471907 demonstrated high, heterogeneous uptake throughout the brain. Of the compartment models, 2T best described [¹⁸F]AS2471907 data. Estimates of V_T were highly correlated between 2T and MA1 (t* = 30 min) with MA1 yielding V_T values ranging from 3.2 ± 1.0 mL/cm³ in the caudate to 15.7 ± 4.2 mL/cm³ in the occipital cortex. The median absolute test-retest variability of 16 ± 5% and high intraclass correlation coefficient (ICC) values of 0.67-0.97 across regions indicate fair test-retest reliability but large intersubject variability. V_T estimates using 180 min were within 10% of estimates using full acquisition time. In summary, [¹⁸F]AS2471907 exhibits reasonable kinetic properties for imaging 11β-HSD1 in human brain.

SUBMITTER: Bhatt S

PROVIDER: S-EPMC7168798 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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First in-human PET study and kinetic evaluation of [18F]AS2471907 for imaging 11β-hydroxysteroid dehydrogenase type 1.

Bhatt Shivani S Nabulsi Nabeel B NB Li Songye S Cai Zhengxin Z Matuskey David D Bini Jason J Najafzadeh Soheila S Kapinos Michael M Ropchan Jim R JR Carson Richard E RE Cosgrove Kelly P KP Huang Yiyun Y Hillmer Ansel T AT

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20190321 4

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes enzymatic conversion of cortisone into the stress hormone cortisol. This first-in-human brain imaging study characterizes the kinetic modeling and test-retest reproducibility of [18F]AS2471907, a novel PET radiotracer for 11β-HSD1. Eight individuals underwent one 180-min (n = 4) or two 240-min (n = 4) [18F]AS2471907 PET brain scans (12 total) acquired on the high-resolution research tomograph (HRRT) ...[more]

PMID: 30895878

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Project description:PurposePositron emission tomography (PET) ligands targeting translocator protein (TSPO) are potential imaging diagnostics of cancer. In this study, we report two novel, high-affinity TSPO PET ligands that are 5,7 regioisomers, [18F]VUIIS1009A ([18F]3A) and [18F]VUIIS1009B ([18F]3B), and their initial in vitro and in vivo evaluation in healthy mice and glioma-bearing rats.ProceduresVUIIS1009A/B was synthesized and confirmed by X-ray crystallography. Interactions between TSPO binding pocket and novel ligands were evaluated and compared with contemporary TSPO ligands using 2D 1H-15N heteronuclear single quantum coherence (HSQC) spectroscopy. In vivo biodistribution of [18F]VUIIS1009A and [18F]VUIIS1009B was carried out in healthy mice with and without radioligand displacement. Dynamic PET imaging data were acquired simultaneously with [18F]VUIIS1009A/B injections in glioma-bearing rats, with binding reversibility and specificity evaluated by radioligand displacement. In vivo radiometabolite analysis was performed using radio-TLC, and quantitative analysis of PET data was performed using metabolite-corrected arterial input functions. Imaging was validated with histology and immunohistochemistry.ResultsBoth VUIIS1009A (3A) and VUIIS1009B (3B) were found to exhibit exceptional binding affinity to TSPO, with observed IC50 values against PK11195 approximately 500-fold lower than DPA-714. However, HSQC NMR suggested that VUIIS1009A and VUIIS1009B share a common binding pocket within mammalian TSPO (mTSPO) as DPA-714 and to a lesser extent, PK11195. [18F]VUIIS1009A ([18F]3A) and [18F]VUIIS1009B ([18F]3B) exhibited similar biodistribution in healthy mice. In rats bearing C6 gliomas, both [18F]VUIIS1009A and [18F]VUIIS1009B exhibited greater binding potential (k 3/k 4)in tumor tissue compared to [18F]DPA-714. Interestingly, [18F]VUIIS1009B exhibited significantly greater tumor uptake (V T) than [18F]VUIIS1009A, which was attributed primarily to greater plasma-to-tumor extraction efficiency.ConclusionsThe novel PET ligand [18F]VUIIS1009B exhibits promising characteristics for imaging glioma; its superiority over [18F]VUIIS1009A, a regioisomer, appears to be primarily due to improved plasma extraction efficiency. Continued evaluation of [18F]VUIIS1009B as a high-affinity TSPO PET ligand for precision medicine appears warranted.

Dataset Information

First in-human PET study and kinetic evaluation of [¹⁸F]AS2471907 for imaging 11β-hydroxysteroid dehydrogenase type 1.

Publications

First in-human PET study and kinetic evaluation of [<sup>18</sup>F]AS2471907 for imaging 11β-hydroxysteroid dehydrogenase type 1.

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