Preclinical evaluation of novel F-18 labeled triazole-substituted amino acids for tumor imaging

Objectives The triazole-substituted amino acid (AA) (S)-[¹⁸F]AFETP has favorable tumor imaging properties and is prepared through the click reaction between an alkyne-substituted AA and 2-[¹⁸F]fluoroethyl azide. Isomeric compounds from the 'reverse' click reaction of azide-substituted AAs have not previously been reported. Our objectives were to prepare novel ¹⁸F-labeled AAs with varying alkyl chain lengths between the α-carbon and the triazole group and to compare their uptake in mice with DBT gliomas.

Methods The click reaction with terminal azide-containing AA precursors and 4-[¹⁸F]fluoro-1-butyne followed by HPLC purification and deprotection provided target ¹⁸F-labeled triazole-substituted AAs (rAFETP, rAFETB, and rAFETPe) in 50-55% yield. Biodistribution studies were conducted in male BALB/c mice with subcutaneous mouse DBT gliomas at 5, 30 and 60 min after injection (n= 4 or 5 at each time point).

Results The three novel tracers demonstrated high uptake in DBT tumors at 5 min (2.6 to 3.6 percent injected dose per gram, %ID/g) and 30 min (1.7 to 2.0 %ID/g) after injection. The tracer with the longest alkyl chain (3 carbons, rAFETPe) demonstrated relatively prolonged retention in DBT tumors (1%ID/g) and most normal tissues including the brain at 60 min. The tracer with intermediate 2-carbon chain length (rAFETB) demonstrated a balance of tumor uptake and tumor to normal tissue ratios with tumor to brain, tumor to blood, and tumor to muscle ratios of 26:1, 8:1 and 2.2:1 at 60 min.

Conclusions The novel ¹⁸F-labeled triazole-substituted AAs were prepared in the good yields through the click reaction using azide-substituted AA precursors. These tracers have promising tumor imaging properties, and alkyl chain length affects their uptake and retention.

Research Support K08CA154790, Mallinckrodt Institute of Radiology