11C-SAM: Radiosynthesis and preliminary biological studies as a potential agent for prostate cancer diagnosis

Objectives Prostate cancer (PCa) is one of the most common solid cancers in men. 11C-choline has proved to be useful for restaging PCa in patients that suffer from biochemical failure with an absolute PSA value of > 1 ng/mL. However, this tracer cannot be recommended as a first-line screening procedure for primary PCa due to its limited sensitivity and its dependency on tumour configuration. High levels of glycine N-methyltransferase (GNMT) have been identified during PCa progression. This enzyme catalyzes the production of sarcosine using S-adenosylmethionine (SAM) as co-enzyme. Therefore, the GNMT overexpression cause an accumulation of sarcosine, metabolite which was characterized as a potentially important metabolic intermediary of cancer cell invasion and aggressivity. The aim of this study is to identify GNMT ligands as potential radiotracers for aggressive PCa diagnosis. For this purpose SAM was labelled with 11C and preliminary biological evaluation was performed, using 11C-choline as reference.

Methods The synthetic process began with the production of 11C-CO2 in the cyclotron (GE PETtrace 16.5MeV) via the 14N(p, α)11C nuclear reaction. 11C-CO2 was delivered from the target to the automated synthetic platform (GE) TRACERlab® FX C Pro, where it was trapped for purification and further reduction to 11C-CH4. Then, it was iodinated to yield 11C-CH3I, having the possibility to be later converted into 11C-CH3OTf in order to react with the precursor, S-adenosylhomocysteine. Several assays were performed testing different labelling conditions in order to obtain 11C-SAM. Crude product from reactor was purified and formulated. Quality control tests included: solution appearance, pH, residual solvents (GC), chemical and radiochemical purity (HPLC), radionucleidic purity and identity, and specific activity. This agent was biologically characterized by the following studies: dynamic PET/CT scans in nude mice (a xenographic human PCa-bearing tumour model) in a preclinical Triumph Tri-modality Scanner (Gamma Medica, Inc.) and biodistribution studies in the same mice model at 10, 30 and 60 min.

Results The optimum conditions for labelling reaction were: 11C-CH3OTf as methylating agent, 5 mg of precursor in formic acid, heating at 60 ºC during 1 min. With this conditions 11C-SAM was obtained as a racemic mixture with a radiochemical purity of (97,4 ± 0,6) % and specific activities of (206,7 - 736,5) GBq/µmol. The preliminary PET/CT studies with 11C-SAM showed an increased specific tumour uptake over contralateral muscle (T/NT) along time, which was higher than 11C-COL. In biodistribution studies 11C-SAM displayed a similar T/NT profile as for image studies.

Conclusions It was possible to optimize the 11C-SAM radiosynthesis, obtaining a tracer that is within the quality control specifications. The preliminary biological studies showed higher T/NT ratio for 11C-SAM compared to 11C-COL, indicating GNMT ligands seem to be very promising compounds for prostate cancer diagnosis. Further studies must be performed in order to obtain a deeper and complete biological characterization of this compound.