PET imaging of the glucagon-like peptide-1 receptor (GLP-1R)
using
radiolabeled exendin is a promising imaging method to detect insulinomas.
However, high renal accumulation of radiolabeled exendin could hamper
the detection of small insulinomas in proximity to the kidneys and
limit its use as a radiotherapeutic agent. Here, we report two new
exendin analogues for GLP-1R imaging and therapy, designed to reduce
renal retention by incorporating a cleavable methionine–isoleucine
(Met-Ile) linker. We examined the renal retention and insulinoma targeting
properties of these new exendin analogues in a nude mouse model bearing
subcutaneous GLP-1R-expressing insulinomas. NOTA or DOTA was conjugated
via a methionine–isoleucine linker to the C-terminus of exendin-4
(NOTA-MI-exendin-4 or DOTA-MI-exendin-4). NOTA- and DOTA-exendin-4
without the linker were used as references. The affinity for GLP-1R
was determined in a competitive binding assay using GLP-1R transfected
cells. Biodistribution of [68Ga]Ga-NOTA-exendin-4, [68Ga]Ga-NOTA-MI-exendin-4, [177Lu]Lu-DOTA-exendin-4,
and [177Lu]Lu-DOTA-MI-exendin-4 was determined in INS-1
tumor-bearing BALB/c nude mice, and PET/CT was acquired to visualize
renal retention and tumor targeting. For all tracers, dosimetric calculations
were performed to determine the kidney self-dose. The affinity for
GLP-1R was in the low nanomolar range (<11 nM) for all peptides.In vivobiodistribution revealed a significantly lower kidney
uptake of [68Ga]Ga-NOTA-MI-exendin-4 at 4 h post-injection
(p.i.) (34.2 ± 4.2 %IA/g), compared with [68Ga]Ga-NOTA-exendin-4
(128 ± 10 %IA/g). Accumulation of [68Ga]Ga-NOTA-MI-exendin-4
in the tumor was 25.0 ± 8.0 %IA/g 4 h p.i., which was similar
to that of [68Ga]Ga-NOTA-exendin-4 (24.9 ± 9.3 %IA/g).
This resulted in an improved tumor-to-kidney ratio from 0.2 ±
0.0 to 0.8 ± 0.3. PET/CT confirmed the findings in the biodistribution
studies. The kidney uptake of [177Lu]Lu-DOTA-MI-exendin-4
was 39.4 ± 6.3 %IA/g at 24 h p.i. and 13.0 ± 2.5 %IA/g at
72 h p.i., which were significantly lower than those for [177Lu]Lu-DOTA-exendin-4 (99.3 ± 9.2 %IA/g 24 h p.i. and 45.8 ±
3.9 %IA/g 72 h p.i.). The uptake in the tumor was 7.8 ± 1.5 and
11.3 ± 2.0 %IA/g 24 h p.i. for [177Lu]Lu-DOTA-MI-exendin-4
and [177Lu]Lu-DOTA-exendin-4, respectively, resulting in
improved tumor-to-kidney ratios for [177Lu]Lu-DOTA-MI-exendin-4.
The new exendin analogues with a Met-Ile linker showed 2–3-fold
reduced renal retention and improved tumor-to-kidney ratios compared
with their reference without the Met-Ile linker. Future studies should
demonstrate whether [68Ga]Ga-NOTA-MI-exendin-4 results
in improved detection of small insulinomas in close proximity to the
kidneys with PET/CT. [177Lu]Lu-DOTA-MI-exendin-4 might
open a window of opportunity for exendin-based radionuclide therapy.