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Synthesis, Preclinical Evaluation, and a Pilot Clinical PET Imaging Study of 68 Ga-Labeled FAPI Dimer.
- Source :
-
Journal of nuclear medicine : official publication, Society of Nuclear Medicine [J Nucl Med] 2022 Jun; Vol. 63 (6), pp. 862-868. Date of Electronic Publication: 2021 Sep 23. - Publication Year :
- 2022
-
Abstract
- Cancer-associated fibroblasts (CAFs) are crucial components of the tumor microenvironment. Fibroblast activation protein (FAP) is overexpressed in CAFs. FAP-targeted molecular imaging agents, including the FAP inhibitors (FAPIs) 04 and 46, have shown promising results in tumor diagnosis. However, these molecules have a relatively short tumor-retention time for peptide-targeted radionuclide therapy applications. We aimed to design a <superscript>68</superscript> Ga-labeled FAPI dimer, <superscript>68</superscript> Ga-DOTA-2P(FAPI) <subscript>2</subscript> , to optimize the pharmacokinetics and evaluate whether this form is more effective than its monomeric analogs. Methods: <superscript>68</superscript> Ga-DOTA-2P(FAPI) <subscript>2</subscript> was synthesized on the basis of the quinoline-based FAPI variant (FAPI-46), and its binding properties were assayed in CAFs. Preclinical pharmacokinetics were determined in FAP-positive patient-derived xenografts using small-animal PET and biodistribution experiments. The effective dosimetry of <superscript>68</superscript> Ga-DOTA-2P(FAPI) <subscript>2</subscript> was evaluated in 3 healthy volunteers, and PET/CT imaging of <superscript>68</superscript> Ga-FAPI-46 and <superscript>68</superscript> Ga-DOTA-2P(FAPI) <subscript>2</subscript> was performed on 3 cancer patients. Results: <superscript>68</superscript> Ga-DOTA-2P(FAPI) <subscript>2</subscript> was stable in phosphate-buffered saline and fetal bovine serum for 4 h. The FAPI dimer showed high affinity and specificity for FAP in vitro and in vivo. The tumor uptake of <superscript>68</superscript> Ga-DOTA-2P(FAPI) <subscript>2</subscript> was approximately 2-fold stronger than that of <superscript>68</superscript> Ga-FAPI-46 in patient-derived xenografts, whereas healthy organs showed low tracer uptake and fast body clearance. The effective dose of <superscript>68</superscript> Ga-DOTA-2P(FAPI) <subscript>2</subscript> was 1.19E-02 mSv/MBq, calculated using OLINDA. Finally, the PET/CT scans of the 3 cancer patients revealed higher intratumoral uptake of <superscript>68</superscript> Ga-DOTA-2P(FAPI) <subscript>2</subscript> than of <superscript>68</superscript> Ga-FAPI-46 in all tumor lesions (SUV <subscript>max</subscript> , 8.1-39.0 vs. 1.7-24.0, respectively; P < 0.001). Conclusion: <superscript>68</superscript> Ga-DOTA-2P(FAPI) <subscript>2</subscript> has increased tumor uptake and retention properties compared with <superscript>68</superscript> Ga-FAPI-46, and it could be a promising tracer for both diagnostic imaging and targeted therapy of malignant tumors with positive expression of FAP.<br /> (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)
Details
- Language :
- English
- ISSN :
- 1535-5667
- Volume :
- 63
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of nuclear medicine : official publication, Society of Nuclear Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 34556528
- Full Text :
- https://doi.org/10.2967/jnumed.121.263016