Design and development of the theranostic pair ¹⁷⁷Lu‐OPS201/⁶⁸Ga‐OPS202 for targeting somatostatin receptor expressing tumors

Abstract

Radiolabeled somatostatin receptor (sstr) antagonists have shown superiority in different preclinical and clinical settings compared with the well‐established and clinically used agonists for targeting sstr‐expressing tumors, with regard to pharmacokinetics, tumor uptake, and retention. The theranostic pair 177Lu‐OPS201/68Ga‐OPS202, based on the sstr2 antagonist JR11 (Cpa‐c[d‐Cys‐Aph(Hor)‐d‐Aph(Cbm)‐Lys‐Thr‐Cys]‐d‐Tyr‐NH2), is the most advanced pair of the antagonist family in terms of preclinical development and is currently under clinical evaluation. OPS201 and OPS202 share the same amino acid sequence (JR11) but feature different conjugated chelators needed for radiolabeling, DOTA for OPS201 and NODAGA for OPS202. In this review, the design and development of the peptidic analog, JR11, and the selection of chelators and radiometals that led to 177Lu‐OPS201/68Ga‐OPS202 are discussed. Furthermore, the preclinical evaluation of both radiolabeled analogs from bench to bedside and the clinical trials involving the theranostic pair are presented.

SPECT Imaging of SST2-Expressing Tumors with 99mTc-Based Somatostatin Receptor Antagonists: The Role of Tetraamine, HYNIC, and Spacers

“…A number of preclinical and initial clinical studies (summarized in [ 17 , 18 ]) suggested improvements in both diagnostic sensitivity and therapeutic efficacy by the use of radiolabeled SST2 antagonists (i.e., DOTA-JR11) instead of agonists (i.e., DOTA-TATE or DOTA-TOC). This was attributed to different reasons, including but not limited to, the following: (a) a higher number of binding sites recognized by the antagonists on the surface of SST-expressing cells [ 19 , 20 ], with consequently higher accumulation; (b) lower uptake of the antagonists in organs that were the primary sites of metastasis (i.e., liver), enabling better lesion-to-background contrast, and as such better image sensitivity [ 4 ]; (c) longer retention of the antagonists in the tumor, leading to higher tumor radiation doses [ 3 , 21 ]; and (d) a higher number of DNA double strand breaks caused by the antagonists on SST-expressing cells [ 22 ], suggesting more effective treatment.…”

Pharmacokinetics, radiation dosimetry, acute toxicity and automated synthesis of [18F]AmBF3-TATE

“…Clinically used SSTR2-targeting positron emission tomography (PET) agents include, but are not limited to, [ 68 Ga]Ga-DOTA-TATE, [ 68 Ga]Ga-DOTA-TOC, and [ 68 Ga]Ga-NODAGA-JR11 [2,3]. These somatostatin analogs can be radiolabeled with beta-emitting radionuclides (e.g., lutetium-177) for peptide receptor radionuclide therapy [4,5].…”

Evaluation of a New 177Lu-Labeled Somatostatin Analog for the Treatment of Tumors Expressing Somatostatin Receptor Subtypes 2 and 5

“…Therefore, each radiotracer needs to be evaluated independently and modifications implemented accordingly to produce a “matching” pair. There are examples in the literature where the theranostic pair consists of two radiotracers that differ not only by the radiometal, but also by the conjugate, e.g., [ 68 Ga]Ga-OPS202/[ 177 Lu]Lu-OPS201 ([ 68 Ga]Ga-NODAGA-JR11/[ 177 Lu]Lu-DOTA-JR11) for SST2 [ 36 ] or 68 Ga-pentixafor/ 177 Lu-pentixather for CXCR4 [ 37 ].…”