PT  - JOURNAL ARTICLE
AU  - Lindner, Thomas
AU  - Altmann, Annette
AU  - Kraemer, Susanne
AU  - Kleist, Christian
AU  - Loktev, Anastasia
AU  - Kratochwil, Clemens
AU  - Giesel, Frederik
AU  - Mier, Walter
AU  - Marme, Frederik
AU  - Debus, Jurgen
AU  - Haberkorn, Uwe
TI  - Design and development of <sup>99m</sup>Tc labeled FAPI-tracers for SPECT-imaging and 188Re therapy.
AID  - 10.2967/jnumed.119.239731
DP  - 2020 Mar 01
TA  - Journal of Nuclear Medicine
PG  - jnumed.119.239731
4099  - http://jnm.snmjournals.org/content/early/2020/03/12/jnumed.119.239731.short
4100  - http://jnm.snmjournals.org/content/early/2020/03/12/jnumed.119.239731.full
AB  - The majority of epithelial tumors recruits fibroblasts and other non-malignant cells and activates them into cancer-associated fibroblasts. This often leads to overexpression of the membrane serine protease fibroblast-activating protein (FAP). It has already been shown that DOTA-bearing FAP inhibitors (FAPIs) generate high contrast images with PET/CT scans. Since SPECT is a lower cost and more widely available alternative to PET, 99mTc-labeled FAPIs represent attractive tracers for imaging applicable in a larger number of patients. Furthermore, the chemically homologous nuclide 188Re is available from generators, which allows FAP-targeted endoradiotherapy. Methods: For the preparation of 99mTc tricarbonyl complexes, a chelator was selected whose carboxylic acids can easily be converted into various derivatives in the finished product. This enabled a platform strategy based on the original tracer. The obtained 99mTc complexes were investigated in vitro by binding and competition experiments on FAP-transfected HT-1080 (HT-1080-FAP) and/or on mouse FAP expressing (HEK-muFAP) and CD26-expressing (HEKCD26) HEK cells and characterized by planar scintigraphy and organ distribution studies in tumor-bearing mice. Furthermore, a first-in-man application was done in two patients with ovarian and pancreatic cancer, respectively. Results: 99mTc-FAPI-19 showed specific binding to recombinant FAP-expressing cells with high affinity. Unfortunately, liver accumulation, biliary excretion and no tumor uptake were observed in the planar scintigraphy of a HT-1080-FAP xenotranplanted mouse. To improve the pharmacokinetic properties hydrophilic amino acids were attached to the chelator moiety of the compound. The resulting 99mTc-labeled FAPI tracers revealed excellent binding properties (up to 45 % binding; above 95 % internalization), high affinity (IC50 = 6.4 nM to 12.7 nM), and significant tumor uptake (up to 5.4 %ID/g) in biodistribution studies. The lead candidate 99mTc-FAPI-34 was applied for diagnostic scintigraphy and SPECT of patients with metastasized ovarian and pancreatic cancer for follow-up to therapy with 90Y-FAPI-46. 99mTc-FAPI-34 accumulated in the tumor lesions also shown in PET/CT imaging using 68Ga-FAPI-46. Conclusion: 99mTc-FAPI-34 represents a powerful tracer for diagnostic scintigraphy, especially in cases where PET imaging is not available. Additionally, the chelator used in this compound allows labeling with the therapeutic nuclide 188Re which is planned for the near future.