Synthesis and preliminary validation of 6-[¹⁸F]-Fluorodopamine ([¹⁸F]FDA) as a PET tracer for neuroblastoma

Objectives Studies have shown better visualization of small sites of pheochromocytoma with [¹⁸18F]FDA over [¹²³]MIBG. [¹⁸F]FDA accumulates via the norepinephrine transporter (NET) and should be useful for other neuroendocrine tumors such as neuroblastoma (NB). We sought to validate this by establishing a reliable synthetic method and analyzing the tracer uptake in vitro and in vivo.

Methods Synthesis of [¹⁸F]FDA was performed using two IBA Syntheras^® following adaptations of methods described by Neumann and DiMagno. The diaryliodonium salt precursor (ALPdopamine) was provided by Ground Fluor Pharmaceuticals. After labeling with K¹⁸F, the complex was decomposed in toluene and deprotected in HI followed by purification by reverse phase HPLC. Cell association studies were performed in SK-N-SH cells (high NET expression) as well as two other NB cell lines: NB1691and CHLA20. [¹⁸F]FDA (1 μCi) was incubated in 6 well plates with 1x10⁶ cells/well. Cells were washed, collected at 2-60 min, and the radioactivity counted (n = 3). A biodistribution study was performed by injection of 150 μCi [¹⁸F]FDA in SCID mice bearing SK-N-SH tumors (n = 3). Mice were sacrificed at 10 min and radioactivity in selected tissues was counted.

Results [¹⁸F]FDA was produced in 53±4 min (RCP = 98.5±3.0%) with high SA (> 250 Ci/mmol) and an uncorrected yield of 16.4±3.0% (n = 4) after HPLC purification and formulation for injection. The cell study showed a greater accumulation of [¹⁸F]FDA in the SK-N-SH cells over the NB1691 (1.8 fold) and CHLA20 (3.8 fold) over 60 min. The biodistribution showed 2.4%ID/g tumor uptake in 10 min. Kidneys were 26.2%ID/g, followed by heart, adrenal gland, blood and liver (14.8, 7.8, 6.8, and 6.3%ID/g, respectively).

Conclusions ALPdopamine provides an effective scaffold for the clinical production of [¹⁸F]FDA. Increased uptake of [¹⁸F]FDA in NB cells of known high NET expression over other NB lines was demonstrated. Expanded biodistribution and small animal imaging studies are currently ongoing following promising tumor uptake and organ clearance.

Research Support Research support was provided by American Lebanese Syrian Associated Charities - St. Jude Children's Research Hospital and Ground Fluor Pharmaceuticals.