⁶⁸ Ga/ ¹⁷⁷ Lu-Labeled Theranostic Pair for Targeting Fibroblast Activation Protein with Improved Tumor Uptake and Retention.

Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE

Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-

Gallium Radioisotopes*/chemistry ; Lutetium*/chemistry ; Radioisotopes*/chemistry; Humans ; Animals ; Mice ; Membrane Proteins/metabolism ; Membrane Proteins/antagonists & inhibitors ; Cell Line, Tumor ; Tissue Distribution ; Endopeptidases/metabolism ; Positron Emission Tomography Computed Tomography ; Radiopharmaceuticals/chemistry ; Radiopharmaceuticals/pharmacology ; Radiopharmaceuticals/pharmacokinetics ; Radiopharmaceuticals/chemical synthesis ; Mice, Nude ; Serine Endopeptidases/metabolism ; Gelatinases/antagonists & inhibitors ; Gelatinases/metabolism ; Theranostic Nanomedicine ; Heterocyclic Compounds, 1-Ring/chemistry ; Female ; Mice, Inbred BALB C

Fibroblast activation protein (FAP) is specifically expressed on cancer-associated fibroblasts in over 90% of tumors and is considered a promising target for cancer theranostics. Here, we developed a novel tracer, DOTA-FAPT, and labeled it with gallium-68 and lutetium-177 as a theranostic pair. [ ⁶⁸ Ga]Ga/[ ¹⁷⁷ Lu]Lu-FAPT exhibited high stability and hydrophilicity, as well as strong affinity to the FAP target. Micro-PET/CT imaging revealed that [ ⁶⁸ Ga]Ga-FAPT exhibited significantly increased uptake in tumors and extended retention in A549-FAP and U87MG tumor xenografts as compared to [ ⁶⁸ Ga]Ga-FAPI-04, demonstrating favorable pharmacokinetic characteristics in vivo. Therapeutic studies showed that [ ¹⁷⁷ Lu]Lu-FAPT had higher tumor accumulation compared to [ ¹⁷⁷ Lu]Lu-FAPI-04, leading to stronger tumor growth inhibition. The first-in-human evaluation also revealed that [ ⁶⁸ Ga]Ga-FAPT has good in vivo distribution and superior diagnostic efficacy on primary and lymph node metastases in a patient with lung cancer. Our encouraging results suggest that ⁶⁸ Ga/ ¹⁷⁷ Lu-labeled DOTA-FAPT is a theranostic pair with broad application prospect.

0 (Gallium Radioisotopes)
5H0DOZ21UJ (Lutetium)
98B30EPP5S (Gallium-68)
EC 3.4.21.- (fibroblast activation protein alpha)
0 (Radioisotopes)
BRH40Y9V1Q (Lutetium-177)
0 (Membrane Proteins)
EC 3.4.- (Endopeptidases)
0 (Radiopharmaceuticals)
EC 3.4.21.- (Serine Endopeptidases)
EC 3.4.24.- (Gelatinases)
0 (Heterocyclic Compounds, 1-Ring)
1HTE449DGZ (1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid)

Date Created: 20240925 Date Completed: 20241010 Latest Revision: 20241010

20241010

10.1021/acs.jmedchem.4c01812

39321030