Paterson Institute for Cancer Research SCIENTIFIC REPORT 2005

RADIOCHEMICAL TARGETING AND IMAGING
an improved toxicity profile, is currently being tested
in phase I clinical studies. As part of this development
we have designed, optimised and validated
a clinical labelling strategy to label the drug with the
positron emitting isotope 124 I. In the renal cancer
patients treated so far, we have shown antigen-specific
accumulation and retention of the labelled
drug in their tumours see figure.
Pharmacokinetics and pharmacodynamics of
anti-angiogenic agents
The aim of this project is to develop an 18 F-labelled
anti-angiogenic agent with validated pharmacodynamic
endpoints by comparing a biological
response, related to the expression of a protein biomarker,
with PET-derived intratumoral concentrations
of the anti-angiogenic agent. As a biomarker
we have synthesised an anti-integrin RGD-peptide
which labelled with fluorine-18 using a novel fluorinating
agent, [ 18 F]-Fluoroacetaldehyde. Unlike previously
developed nucleophilic fluorinating agents,
the advantage of this new compound in reductive
N-alkylation reactions is that the conditions are
mild, water and low temperature compatible, and
can be used in protein radiolabelling.
[ 18 F]Fluoroethyltosylate is produced, with a radioactive
yield ranging from 75 to 90%, from ethylene dip-toluenesulfonate
by fluorination with [ 18 F]FK. It
is then oxidized to [ 18 F]Fluoroacetaldehyde which is
distilled, radioactive yield 60-70%.
[ 18 F]Fluoroacetaldehyde is thus produced in 30 minutes
from [ 18 F]FH coming from the cyclotron target
with an overall radioactive yield ranging from 45 to
63%. This synthesis is easy to automate. Following
the synthesis of the stable N-
Fluoroethylbenzylamine derivative, the new compound
has been characterised by mass spectroscopy
and NMR and serves as a reference compound.
The N-[ 18 F]Fluoroethylbenzylamine is analysed by
HPLC under reverse phase conditions found to
match the reference compound
Radiotracer quantum dots
We have initiated the development of quantum dot
probes to target and image cellular pathways within
tumours and their environment. We have achieved
the synthesis of a new class of quantum dots,
which we term “radiotracer quantum dots”. These
are nanoparticles synthesized from tracer quantities
of imaging and therapeutic radionuclides. We have
demonstrated greater than 90% incorporation of
radioactivity into dots, as well as retention of fluorescence,
stability and other properties of stable
dots. We have demonstrated no toxicity of CdSe
dots at this tracer (nM) level. These multi-functional
particles were localized to various tumour cell
lines where 50-60% uptake was observed within 30
minutes. The radiotracer dots were successfully
injected into animals and the pattern of their localisation
was studied. The non-conjugated dots were
taken up by various tissues predominantly in accordance
with blood flow. We are currently studying
the pattern of accumulation of these nanoparticles
in individual cells and organelles. Our analyses
includes radioimaging, microautoradiography, optical
detection and electron microscopy enabling
therefore multi-modality detection and imaging.
Sagittal, coronal and transaxial PET images captured at 5-6 hours show accumulation of 124I-labelled ANYARA in a destructive
metastatic lesion of the left iliac blade of a renal cell carcinoma patient (arrow). The comparable CT scan is shown for reference.
Non-specific accumulation is also seen in the liver (L), spleen (S) and right kidney (K).
P A T E R S O N I N S T I T U T E S C I E N T I F I C R E P O R T 2 0 0 5
Publications listed
on page 60
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