Introduction: Chemokine receptor-4 (CXCR4) is involved in many diseases (HIV, rheumatoid arthritis, cancer including brain tumors) and is a therapeutic target. A radiolabeled small molecule that readily crosses the blood-brain barrier can aid in early staging of gliomas driven by CXCR4 and could be used to monitor CXCR4-targeted therapy. Following previous studies that showed that dipyrimidine amines are capable of fulfilling this need, a novel [18F]-labeled small molecule was synthesized and evaluated for this application. Experimental: The nonradioactive standards and the nitro precursor used in this study were prepared using established methods. An HPLC method was developed to separate the nitro-precursor from the nonradioactive standard and radioactive product. The nitro-precursor was radiolabeled with 18F under inert, anhydrous conditions using the [18F]-kryptofix 2.2.2 complex to form the desired [18F]-N-(4-(((6-fluoropyridin-2-yl)amino)methyl)benzyl)pyrimidin-2-amine ([18F]-2). The purified radiolabeled compound was used in serum stability, partition coefficient, cellular uptake, and in vivo cancer targeting studies. Results: [18F]-2 was synthesized in 4-10 % decay-corrected yield (to start of synthesis). [18F]-2 (tR ≈ 27 min) was separated from the precursor (tR ≈ 30 min) using a pentafluorophenyl column with an isocratic solvent system. [18F]-2 displayed excellent serum stability. The amount of [18F]-2 bound to the plasma proteins was determined to be &gt; 99%. The partition coefficient (LogD7.6) is 1.25 ± 0.10. Competitive in vitro inhibition indicated 2 does not inhibit uptake of 67Ga- pentixafor. In vitro uptake of [18F]-2 in CXCR4 over-expressing U-87 cells (U-87 CXCR4) was similar to U-87 WT. In vivo studies in a mouse bearing U-87 CXCR4 and U-87 WT tumors on the left and right shoulders were carried out using [18F]-2 and 68Ga-pentixafor on consecutive days. The CXCR4 positive tumor could be clearly visualized using 68Ga-pentixafor, but not with [18F]-2. Conclusions: Our studies indicate [18F]-2 is not an appropriate CXCR4 targeting ligand for imaging CXCR4 expressing tumors, possibly due to the high plasma-protein binding, low cellular uptake, and absence of in vivo targeting. Funding: NIH F32 CA186721 (D.W.D.), NIH R01 CA138468 (J.S.L.), NIH MSKCC Center Grant (P30-CA08748).

Synthesis and evaluation of an 18F-labeled pyrimidine-pyridine amine for targeting CXCR4 receptors in gliomas with intact blood-brain barriers

251st National Meeting (2016)

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