Preclinical Evaluation of ¹⁸F-LMI1195 for In Vivo Imaging of Pheochromocytoma in the MENX Tumor Model

Abstract

We evaluated 18 F-LMI1195 (1-(3-bromo-4-(3-18 F-fluoro-propoxy)benzyl) guanidine), a metaiodobenzylguanidine (MIBG) analog, for the detection of pheochromocytoma in a preclinical in vivo model of endogenous neuroendocrine tumors (multiple endocrine neoplasia [MENX]). Methods: Adrenal uptake kinetics of 18 F-LMI1195 were evaluated in healthy Wistar rats (n 5 6) by dynamic PET imaging. Distribution of 18 F-LMI1195 was evaluated in tumor-bearing MENX mut/mut rats (n 5 10) and control MENX wild-type rats (n 5 4) by biodistribution studies and PET imaging. Biodistribution of 18 F-LMI1195 was compared with 123 I-MIBG in MENX mut/mut rats (n 5 6) and correlated with histological tumor volume and norepinephrine transporter (NET) expression. Uptake specificity was evaluated by in vivo inhibition of the NET by desipramine (n 5 6). Intraadrenal distribution of 18 F-LMI1195 was evaluated by autoradiography. Results: 18 F-LMI1195 showed rapid tracer accumulation in adrenal glands 1 min after tracer injection. Adrenal glands of MENX mut/mut animals showed significantly higher standardized uptake value than MENX wild-type controls (maximum SUV, 10.3 6 2.3 vs. 6.1 6 0.9, P , 0.01). Adrenal uptake in MENX mut/mut rats could be inhibited by desipramine, shown by biodistribution studies (0.06 6 0.01 vs. 0.16 6 0.05 percentage injected dose, P , 0.01), PET imaging (maximum SUV, 3.8 6 0.8 vs. 10.3 6 2.3, P , 0.01), and autoradiography. Adrenal uptake of 18 F-LMI1195 correlated with 123 I-MIBG uptake (r 5 0.91), histological tumor volume (r 5 0.68), and NET expression (r 5 0.50). 18 F-LMI1195 showed an overall favorable distribution for tumor imaging. Conclusion: 18 F-LMI1195 shows high and specific accumulation in pheochromocytomas. Its favorable biodistribution makes it a promising PET tracer for tumor imaging. Further studies are warranted to evaluate its clinical value in oncologic indications.

Initial Evaluation of AF78: a Rationally Designed Fluorine-18-Labelled PET Radiotracer Targeting Norepinephrine Transporter

“…Furthermore, clinical phase 1 trial of [ 18 F]LMI1195 has demonstrated the tolerance and safety in humans but with a higher effective dose than [ 123 I]MIBG [17]. Similar to the application of [ 123 I]MIBG in endocrine tumours, it shows high and specific accumulation in pheochromocytomas, which represented another potential clinical application [37]. Of note, in a recently published comparison of [ 18 F]LMI1195 with [ 11 C]HED, preliminary data suggests a comparable estimates of cardiac sympathetic innervation but offers more favourable kinetics for early cardiac imaging [38], which shows the way to further clinical phase 2 trial in predicting arrhythmic events (NCT03493516).…”

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

“…18 F-LMI1195 was used in imaging of regional cardiac sympathetic denervation in the rabbit model due to its high association with NET (Yu et al 2012). Comparable to either MIBG or HED, LMI1195 has also showed high and specific accumulation in neuroendocrine tumors in the rat model, and more favorably than the reference MIBG (Gaertner et al 2013). Following a successful phase 1 clinical trial, in which 18 F-LMI1195 has demonstrated cardiac imaging potential with comparable radiation dose and favorable kinetics (Sinusas et al 2014), it was compared with 11 C-HED in a recent publication.…”

Animal models of multiple endocrine neoplasia

“…18 F-L-6-fluoro-3,4-dihydroxyphenylalanine ( 18 F-DOPA), targeting the aromatic amino acid transporter and L-amino acid decarboxylase (Hoegerle et al 2002;Havekes et al 2008;Martiniova et al 2012), and 68 Ga-labeled somatostatin analogs (e.g., 68 Ga-DOTATOCand 68 Ga-DOTATATE), targeting somatostatin receptors (Win et al 2007), can also be used to visualize pheochromocytomas in man. We could demonstrate that the rats tumors can be noninvasively visualized using 131 I-MIBG (Gaertner et al 2013), 68 Ga-DOTATOC and 11 C-Hydroxyephedrine (HED; a norepinephrine analog) (Miederer et al 2011), 18 F-DOPA (unpublished), as well as a novel norepinephrine analog, 18 F-LMI1195 (Gaertner et al 2013). For all these tracers, higher uptake was observed in mutant rats bearing adrenomedullary tumors compared to wild-type adrenal glands.…”