Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

Abstract

Introduction Radioiodinated meta-iodobenzylguanidine (MIBG), a norepinephrine transporter (NET) substrate, has been extensively used as an imaging agent to study the pathophysiology of the heart and for the diagnosis and treatment of neuroendocrine tumors. The goal of this study was to develop an 18F-labeled analogue of MIBG that like MIBG itself could be synthesized in a single radiochemical step. Towards this end, we designed 4-fluoropropoxy-3-iodobenzylguanidine (FPOIBG). Methods Standards of FPOIBG and 4-fluoropropoxy-3-bromobenzylguanidine (FPOBBG) as well as their tosylate precursors for labeling with 18F, and a tin precursor for the preparation of radioiodinated FPOIBG were synthesized. Radiolabeled derivatives were synthesized by nucleophilic substitution and electrophilic iododestannylation from the corresponding precursors. Labeled compounds were evaluated for NET transporter recognition in in vitro assays using three NET-expressing cell lines and in biodistribution experiments in normal mice, with all studies performed in a paired-label format. Competitive inhibition of [125I]MIBG uptake by unlabeled benzylguanidine compounds was performed in UVW-NAT cell line to determine IC50 values. Results [18F]FPOIBG was synthesized from the corresponding tosylate precursor in 5.2 ± 0.5% (n = 6) overall radiochemical yields starting with aqueous fluoride in about 105 min. In a paired-label in vitro assay, the uptake of [18F]FPOIBG at 2 h was 10.2 ± 1.5%, 39.6 ± 13.4%, and 13.3 ± 2.5%, in NET-expressing SK-N-SH, UVW-NAT, and SK-N-BE(2c) cells, respectively, while these values for [125I]MIBG were 57.3 ± 8.1%, 82.7 ± 8.9%, and 66.3 ± 3.6%. The specificity of uptake of both tracers was demonstrated by blocking with desipramine. The 125I-labeled congener of FPOIBG gave similar results. On the other hand, [18F]FPOBBG, a compound recently reported in the literature, demonstrated much higher uptake, albeit less than that of co-incubated [125I]MIBG. IC50 values for FPOIBG were higher than that obtained for MIBG and FPOBBG. Unlike the case with [18F]FPOBBG, the heart uptake [18F]FPOIBG in normal mice was significantly lower than that of MIBG. Conclusion Although [18F]FPOIBG does not appear to warrant further consideration as an 18F-labeled MIBG analogue, analogues wherein the iodine in it is replaced with a chlorine, fluorine or hydrogen might be worth pursuing. Advances in knowledge and implications for patient care An 18F-labeled analogue of the well-known radiopharmaceutical MIBG could have significant impact, potentially improving imaging of NET related disease in cardiology and in the imaging of neuroendocrine tumors. Although 18F-labeled analogues of MIBG have been reported including LMI1195, we undertook this work hypothesizing that based on its greater structural similarity to MIBG, FPOIBG might be a better analogue than LMI1195.

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

“…Uptake studies show that the tracer uptake at 2 h was, on average, lower than its lead MIBG, counting 18 F-FPOIBG with10.2, 38.6, and 13.3%, and 125 I-MIBG with 57.3%, 82.7%, and 66.3% in SK-N-SH, UVW-NAT and SK-N-BE(2c) cells, respectively. However, the corresponding bromine analogue of FPOIBG has demonstrated much higher uptake, with a higher IC 50 value than either bromide or MIBG (Vaidyanathan et al 2015). As a result, although FPOIBG does not provide superior in vivo properties than reported tracers, it offers a hint at the structure-activity relationships (SARs) of the tracers, which may prove useful for further tracer design, such as the intolerant iodine and the introduction of 3-fluoropropoxyl substitution consistent with N-[3-bromo-4-(3-fluoro-propoxy)-benzyl]-guanidine (LMI1195).…”

Development of norepinephrine transporter reuptake inhibition assays using SK-N-BE(2)C cells

“…For example, SK-N-BE(2)C cells have been used to examine the relationship between stress and hNET up-regulation [12] , the role of transcription factors in the noradrenergic system (protein levels, NE uptake), [13] and the regulation of hNET gene expression [14] . Due to their high level of hNET expression, SK-N-BE(2)C cells have also been used to evaluate analogues of [ 125 I]MIBG, a radiolabeled norepinephrine analog and NET substrate used clinically to image neuroendocrine tumors [ 15 , 16 ]. All of these published reports collectively indicate that SK-N-BE(2)C cells could serve as a good model system to test reuptake inhibitors.…”

Harnessing Ionic Interactions and Hydrogen Bonding for Nucleophilic Fluorination

“…Among the numerous studies of S N Ar fluorination, diaryliodonium salts containing side chains that are amenable to form hydrogen bonds seem to be the best example to address this question. One such example is the aromatic 18 F-labeling of guanidine-containing radiopharmaceutical [60][61][62][63][64][65][66][67][68][69][70] that was synthesized by nucleophilic fluorination of diaryliodonium salts. Jang and coworkers [71] found that the positions of -Boc protection profoundly affected the efficiency of 18 F-labeling: The fully protected N,N',N¨,N¨-tetrakis-Boc guanidine group (1b in Scheme 4) exhibited remarkably enhanced reactivity (yield = 39% in 5 min) and improved selectivity in contrast to N,N'-bis-Boc protected guanidine (1a, yield ≈ 0) in the absence of hydrogen bonding with fluoride ion (Scheme 4).…”