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

Florian C. Gaertner; Tobias Wiedemann; Behrooz H. Yousefi; Misu Lee; Ines Repokis; Takahiro Higuchi; Stephan G. Nekolla; Ming Yu; Simon Robinson; Markus Schwaiger; Natalia S. Pellegata

doi:10.2967/jnumed.113.119966

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FIGURE 1.
(A and B) Pharmacokinetics of ¹⁸F-LMI1195 in healthy Wistar control rats (n = 6), evaluated by dynamic PET imaging. Maximal adrenal uptake was reached 1 min after injection. Background organs reached low activity after approximately 45 min. (C and D) Maximum-intensity projection of PET images 5 and 45 min after injection. Scale bars represent SUV. Adrenal glands (arrows) can already be delineated well in early PET images (C). Late images show lower background activity; however, bone uptake is increased (D). p.i. = after injection.
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FIGURE 2.
(A–C) ¹⁸F-LMI1195 PET images (maximum-intensity projection) 45 min after injection. Scale bars represent SUV. Normal adrenal glands of MENX wild-type rat show moderate tracer accumulation (A), whereas intense tracer accumulation is observed in adrenal glands of tumor-bearing mut/mut rat (B). After inhibition of NET with desipramine (DMI), tracer uptake in adrenal glands is significantly reduced (C). (D) Quantitative ¹⁸F-LMI1195 PET analysis of MENX wild-type control rats (n = 4), mut/mut rats (n = 10), and mut/mut rats after inhibition of NET with desipramine (n = 6). Bars represent mean SUV_max corrected for partial volume (SUV_max(PV)), mean SUV_max, or mean SUV_mean as indicated in legend. Error bars represent SD. SUV of adrenal glands of mut/mut animals were significantly higher than those of wild-type controls (P < 0.01). After desipramine treatment, SUV of adrenal glands decreased significantly (P < 0.01), whereas significantly higher SUV was observed in liver (P < 0.01).
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FIGURE 3.
(A) Autoradiography of adrenal glands 60 min after injection of ¹⁸F-LMI1195 (top) and corresponding H&E stained slices (bottom). Low tracer uptake is observed in adrenal medulla (black outline in H&E staining) and in outer margin of adrenal cortex of wild-type control animal (left). Inhomogeneous tracer uptake is observed in enlarged adrenal medulla of tumor-bearing mut/mut rat, with focal areas of high tracer accumulation (middle). After desipramine (DMI) injection, virtually no tracer uptake is observed in area of pheochromocytoma in mut/mut animals (right). (B) Densitometry of autoradiography slices shown in A. Bars represent ratio of medulla to cortex of wild-type rat (n = 1), mean ratio of mut/mut animal (n = 2), and mean ratio of desipramine-blocked mut/mut rat (n = 2).
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FIGURE 4.
Biodistribution 60 min after injection of ¹⁸F-LMI1195 in MENX wild-type control rats (n = 4), mut/mut rats (n = 10), and mut/mut rats after desipramine (DMI) treatment (n = 6). (A) Bars represent total tracer uptake in adrenal glands (%ID), and error bars represent SD. (B) Bars represent tracer uptake in remaining organs normalized to organ weight and body weight, and error bars represent SD. When wild-type and nonblocked mut/mut rats were compared, total activity of ¹⁸F-LMI1195 in adrenal glands of mut/mut rats was significantly higher (A, P < 0.01). Furthermore, significant differences were observed for blood and kidneys (B). When nonblocked and blocked mut/mut rats were compared, tracer accumulation in adrenal glands was significantly lower in blocked animals (A). Tracer uptake in liver was significantly higher after desipramine treatment (B). Further significant differences were observed for kidneys, spleen, and bone.
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FIGURE 5.
Biodistribution of ¹⁸F-LMI1195 (n = 10) and ¹²³I-MIBG (n = 6) in tumor-bearing mut/mut rats (60 min after injection). (A) Bars represent total tracer uptake in adrenal glands, and error bars represent SD. No significant differences are observed in adrenal tracer uptake between ¹⁸F-LMI1195 and ¹²³I-MIBG (P > 0.05). (B) Bars represent tracer uptake in remaining organs normalized to organ weight and body weight, and error bars represent SD. Liver uptake of ¹⁸F-LMI1195 was significantly lower than ¹²³I-MIBG (P < 0.01), whereas bone uptake was significantly higher (P < 0.01). Furthermore, significant differences were observed regarding kidneys, spleen, muscle, small intestine, brain, and lung.

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TABLE 1

Biodistribution of ¹⁸F-LMI1195 and ¹²³I-MIBG in MENX Wild-Type Rats and MENX mut/mut Rats With and Without Previous Blocking of NET With Desipramine

	¹⁸F-LMI1195
Parameter	MENX wild-type	MENX mut/mut	MENX mut/mut	¹²³I-MIBG, MENX mut/mut
Time after injection	60 min	60 min	60 min	60 min
Blocking	None	None	Desipramine, 10 mg/kg	None
No. of rats	4	10	6	6
Animal weight	358 ± 101 g	445 ± 95 g	450 ± 115 g	443 ± 99 g
Organ (%ID/g × kg)
Blood	0.044 ± 0.005	0.030 ± 0.008 (P = 0.024^*)	0.024 ± 0.003 (P = 0.18)	0.035 ± 0.008 (P = 0.23)
Heart	0.90 ± 0.20	0.84 ± 0.19 (P = 0.57)	0.73 ± 0.26 (P = 0.42)	0.83 ± 0.11 (P = 0.59)
Liver	0.053 ± 0.012	0.051 ± 0.007 (P = 0.78)	0.34 ± 0.068 (P < 0.001^*)	0.300 ± 0.025 (P = 0.001^*)
Kidney	0.27 ± 0.079	0.35 ± 0.076 (P = 0.025^*)	0.60 ± 0.22 (P = 0.002^*)	0.29 ± 0.12 (P = 0.038^*)
Spleen	0.24 ± 0.060	0.25 ± 0.015 (P = 0.83)	0.10 ± 0.020 (P = 0.002^*)	0.28 ± 0.019 (P = 0.009^*)
Muscle	0.026 ± 0.003	0.025 ± 0.005 (P = 0.48)	0.027 ± 0.004 (P = 0.26)	0.020 ± 0.002 (P = 0.009^*)
Large intestine	0.18 ± 0.030	0.17 ± 0.012 (P = 0.39)	0.20 ± 0.046 (P = 0.39)	0.17 ± 0.014 (P = 0.52)
Small intestine	0.24 ± 0.067	0.31 ± 0.030 (P = 0.088)	0.34 ± 0.046 (P = 0.18)	0.43 ± 0.084 (P = 0.006^*)
Brain	0.012 ± 0.003	0.012 ± 0.005 (P = 0.67)	0.012 ± 0.003 (P = 1.0)	0.006 ± 0.003 (P = 0.037^*)
Lung	0.45 ± 0.11	0.35 ± 0.062 (P = 0.20)	0.29 ± 0.039 (P = 0.18)	0.56 ± 0.10 (P = 0.006^*)
Bone	0.17 ± 0.024	0.21 ± 0.054 (P = 0.20)	0.077 ± 0.010 (P = 0.002^*)	0.034 ± 0.006 (P = 0.004^*)
Adrenal gland (%ID)	0.092 ± 0.023	0.16 ± 0.047 (P < 0.001^*)	0.064 ± 0.013 (P < 0.001^*)	0.15 ± 0.028 (P = 0.60)

↵* Significant P values.
Biodistribution values are %ID ± SD for adrenal glands and %ID/g × kg ± SD for other organs. P values for nonblocked ¹⁸F-LMI1195 in MENX mut/mut rats are with respect to ¹⁸F-LMI1195 in wild-type rats. P values for other 2 categories are with respect to nonblocked ¹⁸F-LMI1195 in mut/mut rats.