99mTc-RP 527, a gastrin releasing peptide (GRP) analogue for visualisation of GRP receptor expressing malignancie: A feasability study

Radiochemical Investigations of 99mTc−N3S-X-BBN[7−14]NH2: An in Vitro/in Vivo Structure−Activity Relationship Study Where X = 0-, 3-, 5-, 8-, and 11-Carbon Tethering Moieties

“…Rink Amide MBHA resin (25 µmole) and Fmoc-protected amino acids, with appropriate side-chain protections, and the Fmoc-protected ω-NH 2 (CH 2 ) n COOH compounds used as spacer groups (75 µmol), were used for SPPS of the nonmetalated BBN conjugates. The preselected synthetic sequence was designed to produce the N 3 S-BBN conjugates with the following general structure DMG-S-C-G-X-Q-W-A-V-G-H-L-M-NH 2 , where the spacer group, X ) 0 (no spacer), ω-NH 2 (CH 2 ) 2 COOH, ω-NH 2 (CH 2 ) 4 COOH, ω-NH 2 (CH 2 ) 7 -COOH, or ω-NH 2 -(CH 2 ) 10 COOH (See Figure 1 for structures of these N 3 S-X-BBN [7][8][9][10][11][12][13][14]NH 2 conjugates). The final products were cleaved by a standard procedure using a cocktail containing thioanisol, water, ethanedithiol and trifluoracetic acid in a ratio of 2:1:1:36 and precipitated into methyl-tert-butyl ether.…”

“…99m Tc-and Re-N 3 S-X-BBN[7-14]NH 2 Conjugate Synthesis. The N 3 S-X-BBN [7][8][9][10][11][12][13][14]NH 2 analogues were labeled with 99m Tc and Re using pre-conjugation, posttransmetalation from 99m Tc(V) 41 or Re(V)-gluconate 42 synthons, respectively (Scheme 1). Preparation of Re(V)-gluconate was performed as previously described.…”

“…Each mixture was heated for 2h at 60°C. After incubation of the resulting solutions at room temperature, the Re-N 3 S-X-BBN [7][8][9][10][11][12][13][14]NH 2 complexes were purified by RP-HPLC. Each of the new complexes were peak-collected and evaporated to dryness.…”

“…Several of these analogues, labeled with radioiodine and radiometals, have been shown to bind selectively and avidly to GRP receptors on cancer cells, both in vitro and in vivo (26)(27)(28)(29)(30)(31)(32)(33)(34)(35). The various BBN analogues studied range from structures in which the radiolabeled moiety is conjugated to the nearly full-length BBN (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) sequence, to where it is attached to a smaller truncated amino acid sequence comprising the GRPreceptor binding moiety (e.g., BBN [8][9][10][11][12][13][14]NH 2 ). Results of studies to evaluate these conjugates demonstrate that radiolabeled BBN/GRP analogues hold important promise as cancer specific radiopharmaceuticals (26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

“…Our laboratory has focused on the design of BBNagonist analogues in which the radiolabeled moiety (e.g., radiometal chelate) is linked either directly to the Nterminal amine group of BBN [7][8][9][10][11][12][13][14]NH 2 or via hydrocarbon spacer groups ( Figure 1) (33)(34)(35)(36)(37)(38). The length and composition of the spacer group, or tether, as well as the physio-chemical properties of the radiolabeled moiety will influence the GRP receptor binding affinity, residualization of radioactivity in cancer cells, and pharmacokinetics of the BBN conjugate (33)(34)(35)(36)(37)(38).…”