Page 118 - Cellular Imaging in Regenerative Medicine, Cancer and Osteoarthritis

Chapter 5
Discussion
The GRPR is overexpressed at high incidence and high density on various tumors, including prostate cancer, making it an appealing molecule for tumor targeting [2]. Over time multiple and promising GRPR targeting radiotracers have been developed, mostly for nuclear imaging and therapeutic purposes. Another interesting approach would be the application of GRPR radioligands for radio-guided surgery since handheld probes and cameras can be used to detect radioactive decay intra-operatively. For GRPR-targeting to be successful, the radiotracer applied should have good in vivo stability, good receptor affinity and favorable pharmacokinetic properties.
In this study we evaluated whether co-administration of the NEP inhibitor PA with [111In]SB3, a radiolabeled GRPR antagonist, leading to in vivo stabilization of the radioligand, would improve the application use of the radiopharmaceutical for pre-operative SPECT/MRI, and the future use of peri-operative scintigraphy and radio-guided surgery. Currently MRI is the most powerful imaging tool for prostate cancer, among other factors because of its high soft-tissue contrast and high resolution [36, 37]. Combining MRI with sensitive and specific targeted nuclear imaging by SPECT potentially improves tumor detection.
Thereto, we performed in vivo stability studies, biodistribution studies and SPECT/MR imaging in healthy mice and mice subcutaneously xenografted with the GRPR-expressing prostate cancer cell line PC-3. Prior to this we confirmed a considerable higher membrane binding compared to internalized fraction of [111In]SB3 as expected for a receptor antagonist. Also we determined the receptor affinity of the unlabeled compound on tissue slices of xenografts generated from the human prostate tumor PC295, confirming previous reported affinities of unlabeled SB3 and natIn labeled SB3 in the low nanomolar range [25]. This data showed that SB3 had excellent affinity for the GRPR, confirming previous findings [11].
In vivo stability studies 5 min p.i. of [111In]SB3 -/+ PA in healthy mice, showed twice as much intact radiopeptide in the blood when PA was co-administered, similar to what has been reported for other radiopeptides [5,
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