Background: Fibroblast activation protein-a (FAP) is a serine protease overexpressed by cancer-associated fibroblasts and linked to poor clinical outcomes.FAP-targeted radiopharmaceuticals enable imaging of metastatic castration-resistant prostate cancer.While 89 Zr-DFO (t 1/2 = 3.27 d) is widely used for immunoPET, many therapeutic agents will rely on DOTA to complex heavier metals with varying coordination chemistries.52g Mn (t 1/2 =5.6 d) offers a half-life suitable for antibodies with long circulation times and potential theranostic pairing.This proof-of-concept study evaluates 52g Mn-DOTA labeling of a fully humanized IgG (huB12), as well as a camelid derived VHH fused to a human IgG scaffold, F7-fc, via DOTA linker, for extended immunoPET imaging.Methods: 52g Mn-DOTA-huB12 or 52g Mn-DOTA-F7fc was injected intravenously in athymic nude mice bearing CWR-R1-EnzR FAP + xenografts.PET/CT imaging was performed daily for up to 13 days using an Inveon system.Tumor uptake was quantified using ROI analysis.Ex vivo biodistribution was assessed by gamma counting and expressed as percent injected activity per gram (% IA/g), with decay correction to injection time.Results: 52g Mn-DOTA-huB12 demonstrated high and sustained tumor uptake, peaking at 9.97 2.2 %IA/g at 6 days post-injection and remaining at 8.68 1.8 % IA/g at day 13.Ex vivo tumor uptake (8.57 0.02 % IA/g) corroborated imaging results.52g Mn-DOTA-F7-Fc showed lower uptake, peaking at 7.85 4.0 %IA/g at 2 days post injection, with ex vivouptake of 8.74 0.04 %IA/g.Minimal bone and muscle uptake for both tracers indicates in vivo stability of the 52g Mn-DOTA complex. Conclusions:Comparative evaluation with 89 Zr-DFO-labeled analogs highlights 52g Mn-DOTA as a stable alternative radiometal for immunoPET, avoiding the in vivo dissociation and off-target bone uptake associated with 89 Zr -DFO complexes.The favorable half-life and DOTA compatibility of 52g Mn make it well suited for imaging antibodies and engineered multi-domain or biparatopic targeting vectors with long circulation times.These results support broader translation of 52g Mn -labeled antibodies beyond FAP, particularly for next-generation theranostic constructs requiring long-lived, macrocycle-chelated PET tracers.
Rizzo et al. (Wed,) studied this question.