Synthesis and evaluation of ¹⁸F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter

Both ¹³¹I- and ¹²³I-labeled meta-iodobenzylguanidine (MIBG) have been widely used in the clinic for targeted imaging of the norepinephrine transporter (NET). The human NET (hNET) gene has been imaged successfully with ¹²⁴I-MIBG positron emission tomography (PET) at time points of >24 h post-injection (p.i.). ¹⁸F-labeled MIBG analogs may be ideal to image hNET expression at time points of <8 h p.i. We developed improved methods for the synthesis of known MIBG analogs, [¹⁸F]MFBG and [¹⁸F]PFBG and evaluated them in hNET reporter gene-transduced C6 rat glioma cells and xenografts.

[¹⁸F]MFBG and [¹⁸F]PFBG were synthesized manually using a three-step synthetic scheme. Wild-type and hNET reporter gene-transduced C6 rat glioma cells and xenografts were used to comparatively evaluate the ¹⁸F-labeled analogs with [¹²³I]/[¹²⁴I]MIBG.

The fluorination efficacy on benzonitrile was predominantly determined by the position of the trimethylammonium group. The para-isomer afforded higher yields (75 ± 7 %) than meta-isomer (21 ± 5 %). The reaction of [¹⁸F]fluorobenzylamine with 1H-pyrazole-1-carboximidamide was more efficient than with 2-methyl-2-thiopseudourea. The overall radiochemical yields (decay-corrected) were 11 ± 2 % (n = 12) for [¹⁸F]MFBG and 41 ± 12 % (n = 5) for [¹⁸F]PFBG, respectively. The specific uptakes of [¹⁸F]MFBG and [¹⁸F]PFBG were similar in C6-hNET cells, but 4-fold less than that of [¹²³I]/[¹²⁴I]MIBG. However, in vivo [¹⁸F]MFBG accumulation in C6-hNET tumors was 1.6-fold higher than that of [¹⁸F]PFBG at 1 h p.i., whereas their uptakes were similar at 4 h. Despite [¹⁸F]MFBG having a 2.8-fold lower affinity to hNET and approximately 4-fold lower cell uptake in vitro compared to [¹²³I]/[¹²⁴I]MIBG, PET imaging demonstrated that [¹⁸F]MFBG was able to visualize C6-hNET xenografts better than [¹²⁴I]MIBG. Biodistribution studies showed [¹⁸F]MFBG and ¹²³I-MIBG had a similar tumor accumulation, which was lower than that of no-carrier-added [¹²⁴I]MIBG, but [¹⁸F]MFBG showed a significantly more rapid body clearance and lower uptake in most non-targeting organs.

[¹⁸F]MFBG and [¹⁸F]PFBG were synthesized in reasonable radiochemical yields under milder conditions. [¹⁸F]MFBG is a better PET ligand to image hNET expression in vivo at 1–4 h p.i. than both [¹⁸F]PFBG and [¹²³I]/[¹²⁴I]MIBG.