J. Med. Chem. 2009, 52, 5299–5302 5299
DOI: 10.1021/jm9008423
Discovery of [18F]N-(2-(Diethylamino)ethyl)-6-
fluoronicotinamide: A Melanoma Positron
Emission Tomography Imaging Radiotracer with
High Tumor to Body Contrast Ratio and Rapid
Renal Clearance
studies have shown that the iodonicotinamide is readily taken
up in melanoma tumors with subsequent melanin binding. The
enhanced hydrophilicity of the pyridine nitrogen may also
allow for a more rapid clearance from the remainder of the
body via renal excretion. Furthermore, the nicotinamide
structure is also amenable to direct nucleophilic substitution
via a rapid, one-step synthesis, providing a high yielding
method for the incorporation of the PET isotope
[18F]fluorine onto these molecules.
Positron emission tomography (PET) has emerged as a
valuable imaging tool due to its ability to provide high
resolution and absolute quantitative uptake in tissue, with
ease in background subtraction versus single photon emission
computed tomography (SPECT) imaging. At present,
2-[18F]fluoro-2-deoxy-D-glucose [18F]FDG PET imaging of
melanoma is the only PET clinical radiotracer used routinely
to localize in melanoma tumors.5 Although [18F]FDG is an
effective tool for melanoma tumor detection, inflammation
and infection decrease its specificity6 and partial volume
effects limits its sensitivity for small volume disease.7
Ivan Greguric,*,† Stephen R. Taylor,† Delphine Denoyer,‡
Patrice Ballantyne,† Paula Berghofer,† Peter Roselt,‡
Tien Q. Pham,† Filomena Mattner,† Thomas Bourdier,†
Oliver C. Neels,‡ Donna S. Dorow,‡ Christian Loc’h,†
Rodney J. Hicks,‡ and Andrew Katsifis†
†Radiopharmaceuticals Research Institute, Australian Nuclear
Science and Technology Organisation, PMB 1, Menai NSW 2234,
Sydney, Australia, and ‡Centre for Molecular Imaging, The Peter
MacCallum Cancer Centre, 12 St. Andrew’s Place, East Melbourne,
VIC 3002, Australia
Received June 10, 2009
Our objective was to incorporate fluorine within the N-
alkyl-nicotinamide structure while retaining high melanin
binding affinity, rapid whole body clearance of unbound
tracer, stability, and ease of radiolabeling. As the nicotin-
amide structure is amendable to direct [18F]fluorination, we
were able to construct a series of fluorine based nicotinamide
compounds that retained the attractive biological properties
displayed with our SPECT analogues.4
Here, we present the discovery of new PET
[18F]fluoronicotinamide radiotracers prepared in one simple
radiosynthetic step. One of them, [18F]N-(2-(diethylamino)-
ethyl)-6-fluoronicotinamide ([18F]2), displayed rapid clear-
ance, superior in vivo stability, and high target to nontarget
ratio as demonstrated by animal PET imaging and biodistri-
bution studies.
The authentic fluorine compounds 2, 4, 6, and 8 and their
precursors 1, 3, 5, and 7 were readily prepared by condensa-
tion of a haloniconitic acid with the appropriate amine
(Scheme 1). Hence, using the chloropyridine heterocycle, it
was possible to introduce the [18F]fluorine atom directly onto
the nicotinic ring by direct [18F]fluorination of the chloro-
nicotinamide precursor and thus avoid a multistep radio-
synthesis such as that reported for the preparation of N-(2-
diethylaminoethyl)-4-[18F]fluorobenzamide ([18F]DAFBA).8
[18F]Fluoronicotinamides [18F]2, [18F]4, [18F]6, and [18F]8
were prepared within 40 min, including HPLC purification
and formulation from their chloronicotinamide precursors.
The resultant [18F]fluoronicotinamides were prepared in
radiochemical yields of 35-55% (nondecay corrected). The
radiotracers were produced in greater than 99% radiochemi-
cal purity and free of UV associated from the chloro-pre-
cursor, as demonstrated by QC analysis. The specific activity
wasinthe rangeof150-220 GBq/μmol and the radiochemical
stability was maintained at >98% over 3-4 h in saline.
The biodistribution of the [18F]fluoronicotinamides was
studied in two mice strains: C57BL/6J black mice bearing
the B16F0 murine melanotic melanoma and BALB/c nude
mice bearing the A375 human amelanotic tumor. In the
B16F0 tumor, at 1 h, the uptake of the N-2-diethylaminoethyl
Abstract: The high melanoma uptake and rapid body clearance
displayed by our series of [123I]iodonicotinamides prompted the
development of
[
18F]N-(2-(diethylamino)ethyl)-6-fluoronicotin-
amide ([18F]2), a novel radiotracer for PET melanoma imaging.
Significantly, unlike fluorobenzoates, [18F]fluorine incorporation
on the nicotinamide ring is one step, facile, and high yielding. [18F]2
displayed high tumor uptake, rapid body clearance via predomi-
nantly renal excretion, and is currently being evaluated in preclinical
studies for progression into clinical trials to assess the responsive-
ness of therapeutic agents.
Skin cancer is the third most common human malignancy
with 2-3 million new cases estimated across the world each
year. Although melanoma accounts for only about 130000 of
these, it is the most dangerous form and results in most of the
deaths related to skin cancer. Survival largely depends on
early detection and cure by surgical resection, as metastatic
malignant melanoma is refractory to most therapies with a
median survival of 6 months and a 5 year survival rate of less
than 5%.1 Despite a paucity of effective treatments currently,
improved diagnostic methods have considerably decreased
mortality rates.
A key feature of melanoma is the extensive pigmentation
present in most tumor cells. Accordingly, this pigmentation is a
very attractive target for both diagnosis and treatment. Radio-
pharmaceutical optimisation programs within our laboratory
and other research groups have resulted in the development of
iodobenzamides to target melanin with high selectivity and
affinity. Radioiodinated (diethylaminoethyl)-iodobenzamides
[
123I]BZA2 and [123I]BZA23 (Figure 1) demonstrated both high
tumor uptake and good clearance from the body, making them
excellent candidates for clinical studies. Our attempts to im-
prove the tumor to background ratios and body clearance
of iodobenzamides and other iodinated melanin binding
compounds led to the development of the corresponding
iodonicotinamide analogues including [123I]N-(2-(diethyl-
amino)ethyl)-5-iodonicotinamide ([123I]MEL008).4 Biological
*To whom correspondence should be addressed. Phone: þ61 2 9717
3759. Fax: þ61 2 9717 9262. E-mail: ivg@ansto.gov.au.
r
2009 American Chemical Society
Published on Web 08/19/2009
pubs.acs.org/jmc
