Improved, one‐pot synthesis of 6‐[¹⁸F]fluorodopamine and quality control testing for use in patients with neuroblastoma

Abstract

6‐[18F]Fluorodopamine ([18F]F‐DA) is taken into cells via the norepinephrine transporter (NET). Recent [18F]F‐DA positron emission tomography–computed tomography (PET‐CT) imaging of adult neuroendocrine tumors shows a dramatic improvement in sensitivity over the standard‐of‐care, meta‐iodobenzylguanidine (MIBG) single‐photon emission computed tomography (SPECT)–CT. A new precursor (ALPdopamine™) allows no‐carrier‐added synthesis resulting in high–molar activity [18F]F‐DA. Automated synthesis of [18F]F‐DA was performed in a single reactor using a two‐step procedure: 1) fluorination via thermolysis of a diaryliodonium salt precursor, followed by 2) acid hydrolysis. Phase transfer agents, Kryptofix 222 and two tetraalkylammonium salts, were investigated. Optimized synthesis of [18F]F‐DA was achieved in 56 to 60 minutes (26% end of synthesis [EOS], nondecay corrected). The product passed all Food and Drug Administration (FDA)–required quality control testing for human use. Accumulation of [18F]F‐DA in SK‐N‐BE(2)‐C (high NET expression) cells was significantly higher than in SH‐EP (minimal NET expression) cells (P < 0.0001). ALPdopamine provides an effective scaffold for the routine production of [18F]F‐DA for human use. Validation of uptake by neuroblastoma (NB) cell lines supports the use of [18F]F‐DA for imaging NB patients. A pediatric NB imaging trial using [18F]F‐DA PET has been approved (Investigational New Drug application (IND) no. 138638) based on the methods reported here. We expect [18F]F‐DA will be localized in NB tumors and that high‐quality functional images will be obtained within minutes after injection.

Improved synthesis of 4‐[18F]fluoro‐m‐hydroxyphenethylguanidine using an iodonium ylide precursor

“…Since our optimized iodonium ylide approach to [ 18 F]4F‐MHPG uses 4.0 mg of TEA + , and the compound is purified using HPLC, it is unlikely that residual TEA + levels would preclude use of the final product in human subjects. Supporting this, a recent report on an improved synthesis of [ 18 F]fluorodopamine for human studies (which uses HPLC purification of the final product) described a QC testing method for TEA + concentrations, which averaged around 50 μg/mL when starting with up to 3.5 mg of tetraethylammonium bicarbonate per reaction …”

Recent advances in radiotracers targeting norepinephrine transporter: structural development and radiolabeling improvements

“…After changing to a nickelmediated radiofluorination method, the yield was improved to 12% (Zlatopolskiey et al 2015). Most recently, the use of iodonium salt as precursor in a one-pot two-step automatic synthesis could increase the yield to 26% (Vāvere et al 2018) that allows the clinical trial of pediatric neuroblastoma imaging (IND 138638).…”

Fast enzymatic synthesis of n.c.a. 6‐[18F]fluorodopamine (FDA) from n.c.a. 6‐[18F]FDOPA and the fate of 6‐FDOPA and 6‐FDA in neuroblastoma and Caki‐1 cells after their uptake

“…Direct synthesis strategies for 6‐[ 18 F]FDA have been described in literature, also with high product yields and molar activities, optimized for various synthesizers. In these cases, of course, dedicated precursors, reagent kits, eventually cassettes and synthesis sequences were needed, whereas with our strategy the widely used 6‐[ 18 F]FDOPA process was applied.…”

“…More specific tracers for neuroblastoma imaging are also considered, among them PET with [ 124 I] m IBG, which can be taken up by the NAT present in most neuroblastoma cells. Other compounds with relation to the catecholamine metabolism of neuroblastoma cells are 6‐[ 18 F]FDA and its precursor 6‐[ 18 F]FDOPA . 6‐[ 18 F]FDA is taken up by the NAT as well by the dopamine transporter in neuroblastoma cells, whereas 6‐[ 18 F]FDOPA as an aromatic amino acid is taken up in many normal and cancer cells by LATs (L‐type neutral amino acid transporters) .…”

“…Instead of scintigraphy with [ 123 I] m IBG, PET could be an interesting alternative for neuroblastoma imaging, eg, with 124 I‐labeled m IBG ([ 124 I] m IBG) . 6‐[ 18 F]Fluorodopamine (6‐[ 18 F]FDA) that is taken up by the DAT and NAT as well as its precursor, 6‐[ 18 F]FDOPA, are also considered for PET in neuroblastoma . In neuroblastoma and other cells of the sympathetic nervous system, dopamine is formed from DOPA by DOPA decarboxylase (AADC, aromatic amino acid decarboxylase).…”