3-O-methyl-6-[¹⁸F]fluoro-L-DOPA - a promising substance for tumour imaging

Because of its potential to image tumour tissue, tumour growth and tumour staging various positron emitter labelled amino acids are utilized (1,2). There is a high clinical interest to overcome various disadvantages of the utilized substances as metabolic decomposition or a high liver uptake. Accordingly we searched for a suitable substance.
The amino acid analogue 3-O-methyl-6-[¹⁸F]fluoro-L-DOPA ([¹⁸F]OMFD) was tested for this purpose. Until now [¹⁸F]OMFD has been used for the correction of PET data measuring dopaminergic functions of the brain with 6-[¹⁸F]fluoro-DOPA (3). Its high yield radiopharmaceutical synthesis and its evaluation by biological methods are described.
Radiopharmaceutical preparation:
For the synthesis of [¹⁸F]OMFD we applied a new precursor, N-formyl-3-O-methyl-4-O-boc-6-trimethylstannyl-L-DOPA-ethylester (4).
Its direct radiofluorination with [¹⁸F]F₂ yields regioselectively only the 6-fluoro isomer.
A partial hydrolysis with concentrated HCl at 140°C for 10 minutes at elevated pressure follows.
[¹⁸F]OMFD is separated from the crude product by isocratic HPLC using isotonic acetat buffer as an eluent at pH 4.7 on an RP-8 column. After sterile filtration the product is ready for use as a radiopharmaceutical.
[¹⁸F]OMFD is available with a radiochemical yield of 20 to 25 % (corrected for decay, related to [¹⁸F]F₂) 50 minutes after EOB. The specific activity is 20 GBq/µmol.
The disadvantage of the electrophilic procedure is the availability of only low activity amount. To overcome this handicap we direct our efforts to a synthesis starting from [¹⁸F]fluoride (5).

First biological evaluation of the radiotracer:

In vitro investigations with HT 29 cells demonstrate the selective uptake primarily by the amino acid transport system L. The incorporation into proteins does not occur. No metabolism was observed in the cells.
In rat and piglet brain only an insignificant share of metabolites in relation to [¹⁸F]OMFD was detected. No evidence for protein incorporation was obtained. In other organs and in plasma the share of metabolites in relation to [¹⁸F]OMFD was maximum 25 %.
Experiments with tumour bearing nude mice showed optimal target to non-target ratios at 60 min p.i. as demonstrated:

tumour to brain 6.5:1
tumour to blood 9.5:1
tumour to muscle 4.6:1

The blood clearance is fast. The liver uptake is comparably low, probably because of lack of protein incorporation.

Interesting results of a first human oncological PET study will be demonstrated.

Summary:

3-O-methyl-6-[¹⁸F]fluoro-L-DOPA is available through a reliable high yield synthesis. The substance seems to be a promising tracer due to its behaviour as an amino acid analogue. It is transported into the cell by the L-transporter and is not incorporated into proteins. It has outstanding target-to-nontarget ratios in organs of interest.