Hesterman_2024_J.Nuc.Med_65_241693

241693 Introduction: Fibroblast activation protein-alpha (FAP) is a membrane-bound dipeptidyl peptidase associated with cancer-associated fibroblasts (CAFs) and activated fibroblasts in tissues undergoing extracellular matrix remodeling. FAP is commonly expressed in the stroma of epithelial-derived cancers and its low expression in normal tissues makes FAP a potential target for both tumor imaging and therapy. LNTH-1363S (alias: RTX-1363S) is a trifunctional small molecule, comprising a FAP-binding ligand, a pharmacokinetics-modulating albumin-binding moiety, and a chelator for incorporation of radiometals. Copper(Cu)-64 is a PET imaging isotope with a half-life of 12.7 hours, making it an advantageous choice for manufacturing and distribution. [Cu-nat]LNTH-1363S is a high affinity FAP inhibitor with a measured IC50 of 0.122 +/- 0.027 nM. This FIH study was intended to determine the safety, biodistribution, and dosimetry of a single dose of [Cu-64]LNTH-1363S in adult healthy volunteers.Methods: For each of six healthy participants (3M, 3F, age range 24-54), [Cu-64]LNTH-1363S was prepared with an average radiochemical yield of 95.8 +/- 1.4% and an average radiochemical purity of 100%. Each participant received a single administration of [Cu-64]LNTH-1363S with mean activity of 5.7 mCi (range 5.5 - 6.0 mCi), equivalent to a mass dose of 90.7 ug (range 80.0 - 97.7 ug).Whole-body PET/CT (skull vertex to thigh) data were acquired 15-30 min, 1 hour (+/- 15 min), 4 hour (+/- 30 min) and 24 hour (+/- 4 hour) post-administration. Regions of interest (liver, kidneys, thyroid, salivary glands, urinary bladder contents, and whole body) were generated for each patient at each time point. Whole-blood samples and urine were collected, and gamma counted in 5 of 6 patients.Dosimetry calculations were performed, following the Medical Internal Radiation Dosimetry (MIRD) formalism. Time-activity curves (TACs) were generated and converted to fraction of administered activity. TACs were fit to exponential models and time-integrated activity coefficients (TIACs) were computed through analytical integration. Urine data were used with the voiding bladder model to estimate bladder TIAC. Blood samples were used to generate red marrow TIAC. TIAC values were entered into OLINDA 2.2.3 software for absorbed dose calculation, using phantom masses scaled according to patient height and weight.Results: No adverse events were observed in this study. No changes in lab parameters were observed post-administration or changes in ECG values. [Cu-64]LNTH-1363S distribution was mainly observed in urinary bladder and kidneys, in keeping with expected excretion pathway of the radiotracer. Some uptake was observed in salivary glands and thyroid. Minimal liver activity was observed, even at 24h post-administration, indicating the stability of the compound in vivo. Figure 1 shows maximum-intensity projections for a representative subject at all imaging time points. Figure 2 displays time-activity curves in units of SUV (decay corrected), averaged across all six subjects.Whole-body effective half-life was 4.86 +/- 0.57 hours. Whole-body effective dose was 0.010 +/- 0.004 mSv/MBq. All values are shown as mean +/- SD unless otherwise noted.The organ receiving the highest absorbed dose was the urinary bladder (median 0.068 mGy/MBq, range 0.054 - 0.242 mGy/MBq). Two subjects had higher urinary bladder absorbed dose than the other subjects, one due to methodological differences and the other due to a uterine fibroid that resulted in rapid urine clearance. All target organs besides urinary bladder wall had an absorbed dose below 0.025 mGy/MBq, including kidneys at 0.022 +/- 0.007 mGy/MBq.Conclusions: [Cu-64]LNTH-1363S was safe when administered as a single dose. Minimal off-target uptake was observed with clearance via kidney and urinary bladder representing the highest normal organ uptake. Normal organ absorbed doses were low. This study supports further development for [Cu-64]LNTH-1363S as a FAP-targeted imaging agent.