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[68Ga]Ga/[177Lu]Lu-BL01, a Novel Theranostic Pair for Targeting C‑X‑C Chemokine Receptor 4
journal contribution
posted on 2019-10-03, 21:17 authored by Joseph Lau, Daniel Kwon, Etienne Rousseau, Zhengxing Zhang, Jutta Zeisler, Carlos F. Uribe, Hsiou-Ting Kuo, Chengcheng Zhang, Kuo-Shyan Lin, François BénardC-X-C
chemokine receptor type 4 (CXCR4) is overexpressed in hematological
and solid malignancies. LY2510924 is a potent peptide antagonist of
CXCR4. A derivative of LY2510924, BL01, was evaluated for theranostic
applications targeting CXCR4. Methods: BL01 was synthesized
by solid phase approach. A Lys(ivDde) residue was added at the C-terminus
of LY2510924 (cyclo[Phe-Tyr-Lys(iPr)-d-Arg-2-Nal-Gly-d-Glu]-Lys(iPr)-NH2). A DOTA chelator was conjugated
to the side chain of the deprotected exogenous Lys residue. The binding
affinity of Ga/Lu-BL01 was determined by competitive radioligand binding
assays. BL01 was radiolabeled with 68GaCl3 or 177LuCl3. Biodistribution studies were performed
in mice bearing Daudi Burkitt’s lymphoma tumor xenografts at
selected time points. PET imaging studies were performed with [68Ga]Ga-BL01, with blocking experiments performed with preinjection
of LY2510924. The stability of [68Ga]Ga/[177Lu]Lu-BL01 was assessed in mouse plasma. Results: Ga-BL01 and Lu-BL01 have nanomolar affinity for CXCR4. [68Ga]Ga-BL01 was obtained in 58 ± 5% decay-corrected radiochemical
yields and >99% radiochemical purity with a molar activity of 40
±
11 GBq/μmol, while [177Lu]Lu-BL01 was obtained in
65 ± 6% decay-corrected radiochemical yields and >99% radiochemical
purity with a molar activity of 120 ± 21 GBq/μmol. [68Ga]Ga-BL01 and [177Lu]Lu-BL01 were excreted primarily
through the renal pathway. Daudi xenografts were clearly delineated
in PET images with good contrast. On the basis of biodistribution
data, tumor uptake of [68Ga]Ga-BL01 was 10.2 ± 2.56%
injected dose per gram (%ID/g) at 1 h postinjection (p.i.). Spleen
(12.6 ± 2.36 %ID/g) and lungs (13.2 ± 2.98 %ID/g), organs
that express CXCR4, had high uptake as well. Preinjection of LY2510924
reduced average uptake of [68Ga]Ga-BL01 in tumors by 88%,
demonstrating target specificity. The uptake of [68Ga]Ga-BL01
in tumor increased to 15.3
± 1.86 %ID/g at 2 h p.i., with improved contrast. [177Lu]Lu-BL01 has similar pharmacokinetics as [68Ga]Ga-BL01
at 1 h p.i. The highest uptake was observed in tumor (14.0 ±
1.11 %ID/g), followed by the lungs (13.0 ± 1.27 %ID/g) and spleen
(11.6 ± 1.78 %ID/g). The tumor uptake increased to 16.2 ±
2.69 %ID/g at 4 h p.i., before declining slightly to 10.1 ± 1.41
%ID/g at 24 h p.i. Both compounds were stable in vivo, as no metabolites
were observed at 5 min p.i. Conclusions: [68Ga]Ga-BL01 and [177Lu]Lu-BL01 are a promising theranostic
pair for imaging and endoradiotherapy of CXCR4-expressing malignancies.