Synthesis, characterization and comparative biodistribution study of a new series of p-Iodine-125 benzamides as potential melanoma imaging agents

doi:10.1016/S0969-8051(01)00242-6

Nuclear Medicine and Biology

Volume 28, Issue 7, October 2001, Pages 799-808

https://doi.org/10.1016/S0969-8051(01)00242-6 Get rights and content

Abstract

Iodobenzamides are reported to possess some affinity for melanoma. In order to identify the compound having the most appropriate pharmacokinetic properties as a potential melanoma imaging agent, thirteen new [¹²⁵I]radioiodobenzamides with a butylene amide-amine spacer and various substituents on the terminal amino group were investigated. Their synthesis, radioiodination and biodistribution in B16 melanoma bearing C57BL6 mice are described and compared to [¹²⁵I] labeled N-(2-diethylaminoethyl)-4-iodobenzamide ([¹²⁵I]BZA), our reference compound. Changes in the terminal amino constituents induced modifications of lipophilicity, tumor uptake and organ distribution. The dimethylaminobutyl iodobenzamide appeared to be the most promising radiopharmaceutical imaging agent for the detection of melanoma and its metastases.

Introduction

Over recent decades, the incidence of malignant melanoma (MM) is increasing at an annual rate of about 7% in most countries, more rapidly in some parts of Australia, and faster than for any other tumors [15]. Malignant melanoma is a tumor with a high potential of metastasis spreading, often early in the disease development but sometimes after a long disease-free period, in particular for the uveal form [19].

Until now, no treatment has demonstrated any significant efficacy although hope arises from immunological and gene therapy under investigation [5]. The early detection of metastases is always an important diagnostic goal and a follow-up is also clinically relevant even for patients without detected proliferation at the surgical removal time of the primary lesion. So, a noninvasive test of high specificity and precision for the detection of melanoma cells is suitable and scintigraphic imaging with a specific radiotracer would be of large interest.

We have been the first to propose a series of iodobenzamide derivatives showing an affinity for melanoma tissue [11], [12]. Preclinical studies reported a selective uptake in melanoma tumors induced in mice, in murine B16 tumors, as well as in human tumors transplanted into athymic mice [4], [8]. A phase II scintigraphic clinical trial evaluating iodine-123 labeled N-(2-diethylaminoethyl)-4-iodobenzamide ([¹²³I]-BZA) as an imaging agent of primary melanomas and metastases conducted on 110 patients resulted in a diagnostic sensitivity of 81% and a specificity of 100% [9].

The interest of this compound for the management of patients with melanoma has been confirmed [1], [2], [16]. The only result of the trial suggesting improvements may be required was the time with the best tumoral definition: 18–24 hr after [¹²³I]BZA administration. For cost and dosimetry reasons, we sought an agent that would provide quality images sooner after injection. With this view, a first series of twelve [¹²⁵I]BZA derivatives has been assessed in melanoma bearing mice [13]. Good results were obtained with para-iodobenzamide structures, and a lengthening of amide-amine spacer appeared favorable.

In order to evaluate systematically a chemical series, we chose to synthesize and study thirteen para-iodobenzamides with a chain length of four methylene groups and varying amino alkyl substituents (Fig. 1 and Table 1).

Section snippets

Materials

All commercially available chemicals were of analytical grade and used without further purification. Sodium [¹²⁵I]iodide was supplied by CIS bio international (Saclay, France) as a no-carrier added solution in reductant-free 0.1N aqueous sodium hydroxide. The melting points (Mp) were determined on a Reichert hot stage apparatus and are uncorrected. Chromatography refers to flash column chromatography on Merck Kieselgel 60 (230–400 mesh) or on Acros neutral Aluminum oxide (50–200 μ) as

Chemistry

All iodobenzamides 1–13 (Table 1) were synthesized, according to two different procedures, from already described aminobutyl amines prepared from readily available starting materials [17].

The primary amino group of N-alkylaminobutylamines was selectively acylated on treating with 4-nitrophenyl 4- iodobenzoate at room temperature for 10 hours, in good yields, to lead to iodobenzamides 1–6 bearing a mono or a disubstituted amino function. On the other hand, iodobenzamides 7–13, with a tertiary

Discussion

The radioiodinated benzamide BZA was the first compound of this chemical class successfully developed as radiotracer agent for the imaging of melanoma and its metastases [8], [9]. In order to propose a more efficient derivative with even better pharmacokinetic characteristics, different structural variations have been realized by changing the position of radioiodine on the phenyl ring, the length of the amide-amine spacer (two or three methylene groups) or the substituents borne by the terminal

Acknowledgements

The authors thank CIS bio international for providing sodium [¹²⁵I]iodide and their support in all the benzamide development.

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Nuclear Medicine and Biology

Abstract

Introduction

Section snippets

Materials

Chemistry

Discussion

Acknowledgements

References (19)

An improved synthesis of N-(diethylaminoethyl)-4-[¹²⁵I]iodobenzamidea potential ligand for imaging malignant melanoma

Nucl. Med. Biol.

Advances in melanoma therapy

J. Am. Acad. Dermatol.

Radioiodinated N-(alkylaminoalkyl)-substituted 4-methoxy-, 4-hydroxy-, and 4-aminobenzamidesbiological investigations for the improvement of melanoma-imaging agents

Nucl. Med. Biol.

Synthesis, radiolabeling, and preliminary evaluation in mice of some (N-diethylaminoethyl)-4-iodobenzamide derivatives as melanoma imaging agents

Nucl. Med. Biol.

Clinical study of [¹²³I] N-(2-diethylaminoethyl)-4-iodobenzamide in the diagnosis of primary and metastatic ocular melanoma

Acta. Ophthalmol. Scand.

N-(2-diethylaminoethyl)-4-[¹²³I]iodobenzamide as a tracer for the detection of malignant melanomasimple synthesis, improved labelling technique and first clinical results

Eur. J. Nucl. Med.

Structure distribution relationship of iodine-123-iodobenzamides as tracers for the detection of melanotic melanoma

J Nucl Med

A new quantitative method to evaluate the biodistribution of a radiolabeled tracer for melanoma using whole-body cryosectioning and a gaseous detectorcomparison with conventional tissue combustion technology

Eur. J. Nucl. Med.

Evaluation in mice of some iodinated melanoma imaging agents using cryosectioning and multi-wire proportional counting

Eur. J. Nucl. Med.

Cited by (44)

Benzamide derivative radiotracers targeting melanin for melanoma imaging and therapy: Preclinical/clinical development and combination with other treatments

Rapid radiosynthesis of two [<sup>18</sup>F]‐labeled nicotinamide derivatives for malignant melanoma imaging

Comparative preclinical evaluation of <sup>68</sup>Ga-NODAGA and <sup>68</sup>Ga-HBED-CC conjugated procainamide in melanoma imaging

Synthesis and characterization of a novel radioiodinated phenylacetamide and its homolog as theranostic agents for malignant melanoma

Synthesis and evaluation of <sup>123</sup><sup>/</sup><sup>131</sup>I-Iochlonicotinamide as a novel SPECT probe for malignant melanoma

The role of chemical elements in melanoma

Synthesis, characterization and comparative biodistribution study of a new series of p-Iodine-125 benzamides as potential melanoma imaging agents

Abstract

Introduction

Section snippets

Materials

Chemistry

Discussion

Acknowledgements

Nucl. Med. Biol.

J. Am. Acad. Dermatol.

Nucl. Med. Biol.

Nucl. Med. Biol.

Clinical study of [123I] N-(2-diethylaminoethyl)-4-iodobenzamide in the diagnosis of primary and metastatic ocular melanoma

Acta. Ophthalmol. Scand.

N-(2-diethylaminoethyl)-4-[123I]iodobenzamide as a tracer for the detection of malignant melanomasimple synthesis, improved labelling technique and first clinical results

Eur. J. Nucl. Med.

Structure distribution relationship of iodine-123-iodobenzamides as tracers for the detection of melanotic melanoma

J Nucl Med

A new quantitative method to evaluate the biodistribution of a radiolabeled tracer for melanoma using whole-body cryosectioning and a gaseous detectorcomparison with conventional tissue combustion technology

Eur. J. Nucl. Med.

Evaluation in mice of some iodinated melanoma imaging agents using cryosectioning and multi-wire proportional counting

Eur. J. Nucl. Med.

Clinical study of [¹²³I] N-(2-diethylaminoethyl)-4-iodobenzamide in the diagnosis of primary and metastatic ocular melanoma

N-(2-diethylaminoethyl)-4-[¹²³I]iodobenzamide as a tracer for the detection of malignant melanomasimple synthesis, improved labelling technique and first clinical results