[68Ga]Ga/[177Lu]Lu-BL01, a Novel Theranostic Pair for Targeting C-X-C Chemokine Receptor 4.

C-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[Plie-TyrLys(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 (GaCl3)-Ga-68 or (LuCl3)-Lu-177. Biodistribution studies were performed in mice bearing Daudi Burkitt's lymphoma tumor xenografts at selected time points. PET imaging studies were performed with [Ga-68]Ga-BL01, with blocking experiments performed with preinjection of LY2510924. The stability of [Ga-68]Ga/[Lu-177]Lu-BL01 was assessed in mouse plasma. Results: Ga-BL01 and Lu-BL01 have nanomolar affinity for CXCR4. [Ga-68]Ga-BL01 was obtained in 58 +/- 5% decay-corrected radiochemical yields and >99% radiochemical purity with a molar activity of 40 +/- 11 GBq/mu mol, while [Lu-177]Lu-BL01 was obtained in 65 +/- 6% decay-corrected radiochemical yields and >99% radiochemical purity with a molar activity of 120 +/- 21 GBq/mu mol. [Ga-68]Ga-BL01 and [Lu-177]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 [Ga-68]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 [Ga-68]Ga-BL01 in tumors by 88%, demonstrating target specificity. The uptake of [Ga-68]Ga-BL01 in tumor increased to 15.3 +/- 1.86 % ID/g at 2 h p.i., with improved contrast. [Lu-177]Lu-BL01 has similar pharmacokinetics as [Ga-68]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: [Ga-68]Ga-BL01 and [Lu-177]Lu-BL01 are a promising theranostic pair for imaging and endoradiotherapy of CXCR4-expressing malignancies.