First-in-human healthy volunteer dosimetry studies of the excitatory amino acid transporter 2 (EAAT2) PET imaging tracer methyl N 4 -(7-[ 18 F]fluoro-9H-fluoren-2-yl)asparaginate, [ 18 F]RP-115.

Objective and Background: The objective of this first-in-human study was to investigate the radiosynthesis, and the preliminary safety, biodistribution, and organ radiation dosimetry of the positron emission tomography (PET) imaging tracer methyl N ⁴ -([ ¹⁸ F]7-fluoro-9H-fluoren-2-yl)asparaginate, known as [ ¹⁸ F]RP-115, in a small cohort (n=8) of healthy volunteers. The [ ¹⁸ F]RP-115 tracer is a methyl ester prodrug and undergoes metabolic saponification in the central nervous system to generate the corresponding carboxylic acid form that selectively binds to the excitatory amino acid transporter 2 (EAAT2) protein.
Procedures and Methods: A multi-step high molar activity tracer radiosynthesis was devised to produce doses. Eight healthy human participants (four male and four female), aged 56-75, received a bolus intravenous injection of [ ¹⁸ F]RP-115 (administered activity range: 70.3-355 MBq) prior to a total of 94 min of PET-MR scanning performed as three sequential scanning sessions. Regional tissue volumes of interest were defined, time-integrated activity coefficients (TIAC) were derived, and then estimates of organ and tissue activities and effective doses (whole body) were calculated, with two versions of OLINDA software (1.1 and 2.0) that incorporated two tissue weighting factor sets (ICRP-60 and -103), respectively.
Main Findings: Tracer was routinely produced in good radiochemical yields and as suitable high molar activity doses for injection. The [ ¹⁸ F]RP-115 injections and PET-MR scans were well-tolerated and no adverse events were reported (≤48 h). Radioactivity was widely biodistributed with good organ uptake. TIACs and estimated radiation organ doses were determined, for which a few statistically significant estimated organ dose differences between males and females were noted. The kidneys were identified as the critical target organ.
Principal Conclusions: Injection of [ ¹⁸ F]RP-115 was considered safe. The estimated kidney radiation doses relative to administered radioactivity identified a more optimal human [ ¹⁸ F]RP-115 tracer injected amount of <211 MBq. This more optimal [ ¹⁸ F]RP-115 tracer injected activity definition is similar to the amounts used for other established [ ¹⁸ F]labeled clinical PET tracers such as [ ¹⁸ F]FDG, and it will be used in future RP-115 clinical PET imaging studies.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors Chi-Kai Chao, John R. Forsayeth and John M. Gerdes have financial interests with Rio Pharmaceuticals, Inc., San Francisco, CA, USA. Author Youngho Seo is Associate Editor for the journal Medical Physics, and on the editorial board for the journal Scientific Reports. Author Henry F. VanBrocklin is Editor-in-Chief for the journal Molecular Imaging. All of the other authors declare they have no competing financial or personal relationship interests.
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